Piperidine derivatives, process for obtaining them and pharmaceutical compositions containing them

ABSTRACT

Piperidine derivatives, process for obtaining them and pharmaceutical compositions containing them, of formula used as neurokinin receptor antagonists, which are, in particular, useful for the treatment of all substance P- and neurokinin-dependent pathologies.

This application is a division of application Ser. No. 08/703,952 filedAug. 28, 1996, now U.S. Pat. No. 5,830,906.

The present invention relates to new piperidine derivatives, to aprocess for preparing them and to pharmaceutical compositions containingthem as active principle.

More especially, the present invention relates to a new class ofpiperidine derivatives for therapeutic use in the pathological phenomenawhich involve the tachykinin system, such as, for example, withoutlimitation and not exclusively: pain (D. Regoli et al., Life Sciences,1987, 40, 109-117), allergy and inflammation (J. E. Morlay et al., LifeSciences, 1987, 41, 527-544), circulatory insufficiency (J. Losay etal., 1977, Substance P, Von Euler, U.S. and Pernow ed. 287-293, RavenPress, New York), gastrointestinal disorders (D. Regoli et al., TrendsPharmacol, Sci., 1985, 6, 481-484), respiratory disorders (J. Mizrahi etal., Pharmacology, 1982, 25, 39-50), neurological disorders andneuropsychiatric disorders (C. A. Maggi et al., J. Autonomic Pharmacol.,1993, 13, 23-93).

In recent years, a large amount of research work has been performed ontachykinins and their receptors. Tachykinins are distributed both in thecentral nervous system and in the peripheral nervous system. Thetachykinin receptors have been recognized and have been classified inthree types: NK₁, NK₂, NK₃. Substance P (SP) is the endogenous ligandfor the NK₁ receptors, neurokinin A (NK_(A)) that for the NK₂ receptorsand neurokinin B (NK_(B)) that for the NK₃ receptors.

NK₁, NK₂ and NK₃ receptors have been demonstrated in various species.

A recent review by C. A. Maggi et al. surveys the tachykinin receptorsand their antagonists and describes the pharmacological studies andapplications in human therapy (J. Autonomic Pharmacol., 1993, 13,23-93).

Among specific antagonists for the NK₁ receptor, the followingnon-peptide compounds may be mentioned: CP-96345 (J. Med. Chem., 1992,3, 2591-2600), RP-68651 (Proc. Natl. Acad. Sci. USA, 1991, 88,10208-10212), SR 140333 (Curr. J. Pharmacol., 1993, 250, 403-413).

For the NK₂ receptor, a non-peptide selective antagonist, SR 48968, hasbeen described in detail (Life Sci., 1992, 5, PL101-PL106).

As regards the NK₃ receptor, some non-peptide compounds have beendescribed as having an affinity for the NK₃ receptor of rat and guineapig brain (FASEB J., 1993, 7 (4), A710, 4104); a peptide antagonist[Trp⁷, βAla⁸ ]NK_(A), weakly specific for the NK₃ receptor of rat brain,has also been described (J. Autonomic Pharmacol., 1993, 13, 23-93).

Patent Application EP-A-336230 describes peptide derivatives which aresubstance P and neurokinin A antagonists and are useful for thetreatment and prevention of asthma.

International Patent Applications WO 90/05525, WO 90/05729, WO 91/09844and WO 91/18899 and European Patent Applications EP-A-0436334,EP-A-0429466 and EP-A-0430771 describe substance P antagonists.

European Patent Applications EP-A-0428434, EP-A-0515240, EP-A-0559538,EP-A-591040, EP-A-0625509, EP-A-0630887 and International PatentApplications WO 94/10146, WO 94/29309, WO 94/26735, WO 95/05377, WO95/12577 and WO 95/16682 describe neurokinin receptor antagonists.

Patent Appliction EP-A-0474561 relates to compounds of formula: ##STR2##in which, in particular, m' is two or three;

R represents hydrogen or a (C₁ -C₆)alkyl;

A₁ can represent a group: ##STR3## in which: Ar' represents anunsubstituted or substituted phenyl; a pyridyl; a thienyl;

x' is zero or one;

x represents a hydroxyl; a (C₁ -C₄)alkoxy; a (C₁ -C₃)alkyl--OH; a (C₁-C₄)acyloxy; a phenacyloxy; a carboxyl; a (C₁ -C₄)alkoxycarbonyl; acyano; an amino(C₁ -C₃)alkylene; a group --N(X₁)₂ in which the groups X₁independently represent hydrogen, a (C₁ -C₄)alkyl; a group --NHCO--(C₁-C₆)alkyl; a group --(C₁ -C₃)alkylene--NHCO--(C₁ -C₃)alkyl; a (C₁-C₄)acyl; a group --S--X₂ in which X₂ represents hydrogen or a (C₁-C₄)alkyl.

Patent Application EP-A-0512901 relates to compounds of formula:##STR4## in which, in particular: m" is two or three;

Q' represents an oxygen atom or two hydrogen atoms;

A₂ can represent a group: ##STR5## in which: Ar"' represents anunsubstituted or substituted phenyl; a pyridyl; a thienyl;

x" is zero or one;

X' represents a hydrogen; a hydroxyl; a (C₁ -C₄)alkoxy; a carboxyl; a(C₁ -C₄)alkoxycarbonyl; a cyano; a group --N(X'₁)₂ in which the groupsX'₁ independently represent hydrogen, a (C₁ -C₄)alkyl, a hydroxy-(C₁-C₄)alkyl, a (C₁ -C₄)acyl, or alternatively --(X'₁)₂, with the nitrogenatom to which it is linked, constitutes a heterocycle chosen frompyrrolidine, piperidine and morpholine; a group --S--X'₂ in which X'₂represents hydrogen or a (C₁ -C₄)alkyl group.

It has now been found that new piperidine derivatives possessadvantageous pharmacological properties as neurokinin receptorantagonists, and are, in particular, useful for the treatment of allsubstance P- and neurokinin-dependent pathologies.

Furthermore, it has been found that these new piperidine derivativeswhich are substituted at position 4 with new functions other than thosedescribed previously for the compounds of formula 1 or the compounds offormula 2 possess a very high affinity for the neurokinin receptors.

Thus, according to one of its aspects, the present invention relates tocompounds of formula: ##STR6## in which: x is zero or one;

R₁ represents hydrogen;

R₂ represents a hydrogen or a (C₁ -C₇)alkyl;

or alternatively R₁ and R₂ together constitute a group --(CH₂)_(n) CQ--in which Q represents an oxygen atom or two hydrogen atoms and n is one,two or three;

Y represents a group chosen from:

Y₁) (C₁ -C₇)alkyl;

Y₂) --(CH₂)_(p) --OR₃ ;

Y₃) --O--CH₂ CH₂ --OR₄ ;

Y₄) --OCOR₅ ;

Y₅) --(CH₂)_(p) --OCOR₆ ;

Y₆) --CH₂)_(q) --OCONH--(C₁ -C₇)alkyl;

Y₇) --NR₇ R₈ ;

Y₈) --(CH₂)_(p) --NR₉ R₁₀ ;

Y₉) --NR₁₁ C(═W₁)R₁₂ ;

Y₁₀) --(CH₂)_(p) --NR₁₃ C(═W₁)R₁₄ ;

Y₁₁) --(CH₂)_(q) --NR₁₃ COOR₁₅ ;

Y₁₂) --CH₂)_(q) --NR₁₃ SO₂ R₁₆ ;

Y₁₃) --(CH₂)_(q) --NR₁₃ C(═W₁)NR₁₇ R₁₈ ;

Y₁₄) --C(═W₁)NR₁₉ R₂₀ ;

Y₁₅) --CH₂ --COOR₂₁ ;

Y₁₆) --CH₂ --C(═W₁)NR₁₇ R₁₈ ;

Y₁₇) ##STR7## Y₁₈) ##STR8## Y₁₉) --CO--NR₂₅ --NR₂₆ R₂₇ ; Y₂₀) --NR₂₅COCOR₂₉ ;

Y₂₁) ##STR9## in which groups: p is one or two;

q is zero, one or two;

W₁ represents an oxygen atom or a sulphur atom;

R₃ represents a (C₃ -C₇)alkyl; R₃ can, in addition, represent hydrogenwhen R₁ and R₂ together constitute a group --(CH₂)_(n) --CQ--;

R₄ represents a hydrogen; (C₁ -C₇)alkyl; a formyl; a (C₁-C₇)alkylcarbonyl;

R₅ represents a pyridyl or a (C₃ -C₇)cycloalkyl unsubstituted orsubstituted with one or more methyls; R₅ can, in addition, represent aphenyl when R₁ and R₂ together constitute a group --(CH₂)_(n) --CQ--;

R₆ represents hydrogen; a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkylunsubstituted or substituted with one or more methyls; a phenyl; apyridyl;

R₇ represents a hydrogen or a (C₁ -C₇)alkyl;

R₈ represents a (C₃ -C₇)cycloalkylmethyl; a benzyl;

or alternately R₇ and R₈, together with the nitrogen atom to which theyare linked, constitute a heterocycle chosen from: azetidine,thiomorpholine, perhydroazepine, piperazine unsubstituted or substitutedat position 4 with a (C₁ -C₄)alkyl; R₇ and R₈, together with thenitrogen atom to which they are linked, can, in addition, constitute aheterocycle chosen from pyrrolidine, piperidine and morpholine when R₁represents hydrogen;

R₉ represents a hydrogen or a (C₁ -C₇)alkyl;

R₁₀ represents a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkylmethyl; a benzyl;R₁₀ can, in addition, represent hydrogen when R₁ and R₂ togetherconstitute a group --(CH₂)_(n) --CQ--;

R₁₁ represents a hydrogen or a (C₁ -C₇)alkyl;

R₁₂ represents a (C₃ -C₇)cycloalkyl unsubstituted or substituted withone or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; athienyl; a pyrrolyl; an imidazolyl; R₁₂ can, in addition, representhydrogen when R₁ represents hydrogen; R₁₂ can, in addition, represent a(C₁ -C₇)alkyl when both R₁₁ represents a (C₁ -C₇)alkyl and R₁ representshydrogen;

or alternatively R₁₁ and R₁₂ together represent a group --(CH₂)_(m) --in which m is three or four;

R₁₃ represents a hydrogen or a (C₁ -C₇)alkyl;

R₁₄ represents a hydrogen; a (C₃ -C₇)cycloalkyl unsubstituted orsubstituted with one or more methyls; a phenyl, a benzyl, a vinyl; apyridyl; a furyl; a thienyl; a pyrrolyl; an imidazolyl; R₁₄ can, inaddition, represent a (C₁ -C₇)alkyl when R₁ and R₂ together constitute agroup --(CH₂)_(n) --CQ--; R₁₄ can, in addition, represent a (C₁-C₇)alkyl when both R₁₃ represents a (C₁ -C₇)alkyl and R₁ representshydrogen;

R₁₅ represents a (C₁ -C₇)alkyl or a phenyl;

R₁₆ represents a (C₁ -C₇)alkyl; an amino, free or substituted with oneor two (C₁ -C₇)alkyls; a phenyl unsubstituted or substituted one or moretimes with a substituent chosen from: a halogen atom, a (C₁ -C₇)alkyl, atrifluoromethyl, a hydroxyl, a (C₁ -C₇)alkoxy, a carboxyl, a (C₁-C₇)alkoxycarbonyl, a (C₃ -C₇)alkylcarbonyloxy, a cyano, a nitro, anamino, free or substituted with one or two (C₁ -C₇)alkyls, the saidsubstituents being identical or different;

R₁₇ and R₁₈ each independently represent a hydrogen or a (C₁ -C₇)alkyl;R₁ can, in addition, represent a (C₃ -C₇)cycloalkyl, a (C₃-C₇)cycloalkylmethyl, a hydroxyl, a (C₁ -C₄)alkoxy, a benzyl or aphenyl;

or alternatively R₁₇ and R₁₈, together with the nitrogen atom to whichthey are linked, constitute a heterocycle chosen from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine andpiperazine unsubstituted or substituted at position 4 with a (C₁-C₄)alkyl;

R₁₉ represents a hydrogen or a (C₁ -C₇)alkyl;

R₂₀ represents a (C₃ -C₇)cycloalkyl; a (C₃ -C₇)cycloalkylmethyl; ahydroxyl; a (C₁ -C₄)alkoxy; a benzyl; a phenyl; R₂₀ can, in addition,represent a hydrogen or a (C₁ -C₇)alkyl when R₁ represents hydrogen orwhen R₁ and R₂ together constitute a group --(CH₂)_(n) --CQ-- in which nis two or three;

or alternatively R₁₉ and R₂₀, together with the nitrogen atom to whichthey are linked, constitute a heterocycle chosen from azetidine,thiomorpholine, perhydroazepine, piperazine and isoxazolidine; R₁₉ andR₂₀, together with the nitrogen atom to which they are linked, can, inaddition, constitute a heterocycle chosen from pyrrolidine, piperidine,morpholine and piperazine substituted at position 4 with a (C₁ -C₄)alkylwhen R₁ represents hydrogen or when R₁ and R₂ together constitute agroup (CH₂)_(n) --CQ-- in which n is two or three;

R₂₁ represents a hydrogen or a (C₁ -C₇)alkyl;

R₂₂ represents a hydrogen or a (C₁ -C,)alkyl;

R₂₃ and R₂₄ each independently represent a hydrogen or a (C₁ -C₇)alkyl;R₂₄ can, in addition, represent a formyl or a (C₁ -C₇)alkylcarbonyl;

R₂₅ represents a hydrogen or a (C₁ -C₇)alkyl;

R₂₆ and R₂₇ each independently represent a hydrogen or a (C₁ -C₇)alkyl;R₂₇ can, in addition, represent a (C₁ -C₇)alkylcarbonyl;

or alternatively R₂₆ and R₂₇, together with the nitrogen atom to whichthey are linked, constitute a heterocycle chosen from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine or perhydroazepine;

R₂₉ represents a (C₁ -C₄)alkoxy;

Ar₁ represents a phenyl unsubstituted or substituted one or more timeswith a substituent chosen from: a halogen atom, a hydroxyl, a (C₁-C₄)alkoxy, a (C₁ -C₄)alkyl, a trifluoromethyl, a methylenedioxy, thesaid substituents being identical or different; a thienyl unsubstitutedor substituted with a halogen atom; a benzothienyl unsubstituted orsubstituted with a halogen atom; a naphthyl unsubstituted or substitutedwith a halogen atom; an indolyl unsubstituted or N-substituted with a(C₁ -C₄)alkyl or a benzyl; an imidazolyl unsubstituted or substitutedwith a halogen atom; a pyridyl unsubstituted or substituted with ahalogen atom; a biphenyl;

Ar₂ represents a phenyl unsubstituted or substituted one or more timeswith a substituent chosen from: a halogen atom, a hydroxyl, a (C₁-C₄)alkoxy, a (C₁ -C₄)alkyl, a trifluoromethyl, a methylenedioxy, thesaid substituents being identical or different; a pyridyl; a thienyl, apyrimidinyl; an imidazolyl unsubstituted or substituted with a (C₁-C₄)alkyl;

T represents a --CH₂ -- group; a --CO-- group; a --COO-- group; a group--CONR₂₈ -- in which R₂₈ represents a hydrogen or a (C₁ -C₄)alkyl; onthe condition that T represents a --CH₂ -- group when Q represents anoxygen atom and T represents one of the groups --CO--, --COO-- or--CONR₂₈ -- when Q represents two hydrogen atoms;

A represents a direct bond or a group --(CH₂)_(t) -- in which t is one,two or three;

Z represents an optionally substituted mono-, di- or tricyclic aromaticor heteroaromatic group; as well as their possible salts with inorganicor organic acids.

The compounds of formula (I) according to the invention comprise boththe optically pure isomers and the racemates.

Salts of the compounds of formula (I) may be formed. These saltscomprise both those with inorganic or organic acids which permit anappropriate separation or crystallization of the compounds of formula(I), such as picric acid or oxalic acid or an optically active acid, forexample a mandelic or camphorsulphonic acid, and those which formpharmaceutically acceptable salts such as the hydrochloride,hydrobromide, sulphate, hydrogen sulphate, dihydrogen phosphate,methanesulphonate, methyl sulphate, maleate, fumarate,2-naphthalenesulphonate, gluconate, citrate, isethionate,benzenesulphonate and paratoluenesulphonate.

Depending on the meaning of R₁ and R₂, the compounds of the inventionbelong to one of the families described below, of formula (Ia), (Ib) or(Ic).

The family (Ia) consists of the compounds of formula: ##STR10## inwhich: x, Ar₁, Ar2, T, A and Z have the meanings given above for (I);

R₂ represents a hydrogen or a (C₁ -C₇)alkyl;

Y represents a group chosen from:

Y₁) (C₁ -C₇)alkyl;

Y₂) --(CH₂)_(p) --OR₃ ;

Y₃) --O--CH₂ CH₂ --OR₄ ;

Y₄) --OCOR₅ ;

Y₅) --(CH₂)_(p) --OCOR₆ ;

Y₆) --(CH₂)_(q) --OCONH--(C₁ -C₇)alkyl;

Y₇) --NR₇ R₈ ;

Y₈) --(CH₂)_(p) --NR₉ R₁₀ ;

Y₉) --NR₁₁ C(═W₁)R₁₂ ;

Y₁₀) --(CH₂)_(p) --NR₁₃ C(═W₁)R₁₄ ;

Y₁₁) --(CH₂)_(q) --NR₁₃ COOR₁₅ ;

Y₁₂) --(CH₂)_(q) --NR₁₃ SO₂ R₁₆ ;

Y₁₃) --CH₂)_(q) --NR₁₃ C(═W₁)NR₁₇ R₁₈ ;

Y₁₄) --C(═W₁)NR₁₉ R₂₀ ;

Y₁₅) --CH₂ -COOR₂₁ ;

Y₁₆) --CH₂ -- C(═W₁)NR₁₇ R₁₈ ;

Y₁₇) ##STR11## Y₁₈) ##STR12## Y₁₉) --CO--NR₂₅ --NR₂₆ R₂₇ Y₂₀) --NR₂₅COCOR₂₉ ;

Y₂₁) ##STR13## in which groups: p is one or two;

q is zero, one or two;

W₁ represents an oxygen atom or a sulphur atom;

R₃ represents a (C₁ -C₇)alkyl;

R₄ represents a hydrogen; a (C₁ -C₇)alkyl; a formyl; a (C₁-C₇)alkylcarbonyl;

R₅ represents a pyridyl or a (C₃ -C₇)cycloalkyl unsubstituted orsubstituted with one or more methyls;

R₆ represents hydrogen; a (C₁ -C₇)alkyl; a(C₃ -C₇)cycloalkylunsubstituted or substituted with one or more methyls; a phenyl; apyridyl;

R₇ represents a hydrogen or a (C₁ -C₇)alkyl;

R₈ represents a (C₃ -C₇)cycloalkylmethyl; a benzyl;

or alternately R₇ and R₈, together with the nitrogen atom to which theyare linked, constitute a heterocycle chosen from: azetidine,thiomorpholine, perhydroazepine, piperazine unsubstituted or substitutedat position 4 with a (C₁ -C₄)alkyl, pyrrolidine, piperidine ormorpholine;

R₉ represents a hydrogen or a (C₁ -C₇)alkyl;

R₁₀ represents a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkylmethyl; a benzyl;

R₁₁ represents a hydrogen or a (C₁ -C₇)alkyl;

R₁₂ represents a (C₃ -C₇)cycloalkyl unsubstituted or substituted withone or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; athienyl; a pyrrolyl; an imidazolyl; a hydrogen; R₁₂ can, in addition,represent a (C₁ -C₇)alkyl when R₁₁ represents a (C₁ -C₇)alkyl;

or alternatively R₁₁ and R₁₂ together represent a group --(CH₂)_(m) --in which m is three or four;

R₁₃ represents a hydrogen or a (C₁ -C₇)alkyl;

R₁₄ represents a hydrogen; a (C₃ -C₇)cycloalkyl unsubstituted orsubstituted with one or more methyls; a phenyl; a benzyl; a vinyl; apyridyl; a furyl; a thienyl; a pyrrolyl; an imidazolyl; R₁₄ can, inaddition, represent a (C₁ -C₇)alkyl when R₁₃ represents a (C₁ -C₇)alkyl;

R₁₅ represents a (C₁ -C₇)alkyl or a phenyl;

R₁₆ represents a (C₁ -C₇)alkyl; an amino, free or substituted with oneor two (C₁ -C₇)alkyls; a phenyl unsubstituted or substituted one or moretimes with a substituent chosen from: a halogen atom, a (C₁ -C₇)alkyl, atrifluoromethyl, a hydroxyl, a (C₁ -C₇)alkoxy, a carboxyl, a (C₁-C₇)alkoxycarbonyl, a (C₁ -C₇)alkylcarbonyloxy, a cyano, a nitro, anamino, free or substituted with one or two (C₁ -C₇)alkyls, the saidsubstituents being identical or different;

R₁₇ and R₁₈ each independently represent a hydrogen or a (C₁ -C₇)alkyl;R₁₈ can, in addition, represent a (C₃ -C₇)cycloalkyl, a (C₃-C₇)cycloalkylmethyl, a hydroxyl, a (C₁ -C₄)alkoxy, a benzyl or aphenyl;

or alternatively R₁₇ and R₁₈, together with the nitrogen atom to whichthey are linked, constitute a heterocycle chosen from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine andpiperazine unsubstituted or substituted at position 4 with a (C₁-C₄)alkyl;

R₁₉ represents a hydrogen or a (C₁ -C₇)alkyl;

R₂₀ represents a (C₃ -C₇)cycloalkyl; a (C₃ -C₇)cycloalkylmethyl; ahydroxyl; a (C₁ -C₄)alkoxy; a benzyl; a phenyl; a hydrogen; a (C₁-C₇)alkyl;

or alternatively R₁₉ and R₂₀, together with the nitrogen atom to whichthey are linked, constitute a heterocycle chosen from: azetidine,thiomorpholine, perhydroazepine, piperazine, isoxazolidine, pyrrolidine,piperidine, morpholine and piperazine substituted at position 4 with a(C₁ -C₄)alkyl;

R₂₁ represents a hydrogen or a (C₁ -C₇)alkyl;

R₂₂ represents a hydrogen or a (C₁ -C₇)alkyl;

R₂₃ and R₂₄ each independently represent a hydrogen or a (C₁ -C₇)alkyl;R₂₄ can, in addition, represent a formyl or a (C₁ -C₇)alkylcarbonyl;

R₂₅ represents a hydrogen or a (C₁ -C₇)alkyl;

R₂₆ and R₂₇ each independently represent a hydrogen or a (C₁ -C₇)alkyl;R₂₇ can, in addition, represent a (C₁ -C₇)alkylcarbonyl;

or alternatively R₂₆ and R₂₇, together with the nitrogen atom to whichthey are linked, constitute a heterocycle chosen from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine and perhydroazepine;

R₂₉ represents a (C₁ -C₄)alkoxy; as well as their possible salts withinorganic or organic acids.

The family (Ib) consists of the compounds of formula: ##STR14## in whichx, Ar₁, Ar2, n, A and Z have the meanings given above for (I);

Y represents a group chosen from:

Y₁) (C₁ -C₇)alkyl;

Y₂) --(CH₂)_(p) --OR₃ ;

Y₃) --O--CH₂ CH₂ --OR₄ ;

Y₄) --OCOR₅ ;

Y₅) --(CH₂)_(p) --OCOR₆ ;

Y₆) --(CH₂)_(q) --OCONH--(C₁ -C₇)alkyl;

Y₇) --NR₇ R₈ ;

Y₈) --(CH₂)_(p) --NR₉ R₁₀ ;

Y₉) --NR₁₁ C(═W₁)R₁₂ ;

Y₁₀) --(CH₂)_(p) --NR₁₃ C(═W₁)R₁₄ ;

Y₁₁) --(CH₂)_(q) --NR₁₃ COOR₁₅ ;

Y₁₂) --(CH₂)_(q) --NR₁₃ SO₂ R₁₆ ;

Y₁₃) --(CH₂)_(q) --NR₁₃ C(═W₁)NR₁₇ R₁₈ ;

Y₁₄) --C(═W₁)NR₁₉ R₂₀ ;

Y₁₅) --CH₂ --COOR₂₁ ;

Y₁₆) --CH₂ --C(═W₁)NR₁₇ R₁₈ ;

Y₁₇) ##STR15## Y₁₈) ##STR16## Y₁₉) --CO--NR₂₅ --NR₂₆ R₂₇ ; Y₂₀) --NR₂₅COCOR₂₉ ;

Y₂₁) ##STR17## in which groups: p is one or two;

q is zero, one or two;

W₁ represents an oxygen atom or a sulphur atom;

R₃ represents a hydrogen or a (C₁ -C₇)alkyl;

R₄ represents a hydrogen; a (C₁ -C₇)alkyl; a formyl; a (C₁-C₇)alkylcarbonyl;

R₅ represents a pyridyl; a (C₃ -C₇)cycloalkyl unsubstituted orsubstituted with one or more methyls; a phenyl;

R₆ represents hydrogen; a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkylunsubstituted or substituted with one or more methyls; a phenyl; apyridyl;

R₇ represents a hydrogen or a (C₁ -C₇)alkyl;

R₈ represents a (C₃ -C₇)cycloalkylmethyl; a benzyl;

or alternately R₇ and R₈, together with the nitrogen atom to which theyare linked, constitute a heterocycle chosen from: azetidine,thiomorpholine, perhydroazepine, piperazine unsubstituted or substitutedat position 4 with a (C₁ -C₄)alkyl;

R₉ represents a hydrogen or a (C₁ -C₇)alkyl;

R₁₀ represents a hydrogen; a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkylmethyl;a benzyl;

R₁₁ represents a hydrogen or a (C₁ -C₇)alkyl;

R₁₂ represents a (C₃ -C₇)cycloalkyl unsubstituted or substituted withone or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; athienyl; a pyrrolyl; an imidazolyl;

or alternatively R₁₁ and R₁₂ together represent a group --(CH₂)_(m) --in which m is three or four;

R₁₃ represents a hydrogen or a (C₁ -C₇)alkyl;

R₁₄ represents a hydrogen; a (C₃ -C₇)cycloalkyl unsubstituted orsubstituted with one or more methyls; a phenyl; a benzyl; a vinyl; apyridyl; a furyl; a thienyl; a pyrrolyl; an imidazolyl; a (C₁ -C₇)alkyl

R₁₅ represents a (C₁ -C₇)alkyl or a phenyl;

R₁₆ represents a (C₁ -C₇)alkyl; an amino, free or substituted with oneor two (C₁ -C₇)alkyls; a phenyl unsubstituted or substituted one or moretimes with a substituent chosen from: a halogen atom, a (C₁ -C₇)alkyl, atrifluoromethyl, a hydroxyl, a (C₁ -C₇)alkoxy, a carboxyl, a (C₁-C₇)alkoxycarbonyl, a (C₁ -C₇)alkylcarbonyloxy, a cyano, a nitro, anamino, free or substituted with one or two (C₁ -C₇)alkyls, the saidsubstituents being identical or different;

R₁₇ and R₁₈ each independently represent a hydrogen or a (C₁ -C₇)alkyl;R₁₈ can, in addition, represent a (C₃ -C₇)cycloalkyl, a (C₃-C₇)cycloalkylmethyl, a hydroxyl, a (C₁ -C₄)alkoxy, a benzyl or aphenyl;

or alternatively R₁₇ and R₁₈, together with the nitrogen atom to whichthey are linked, constitute a heterocycle chosen from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine andpiperazine unsubstituted or substituted at position 4 with a (C₁-C₄)alkyl;

R₁₉ represents a hydrogen or a (C₁ -C₇)alkyl;

R₂₀ represents a (C₃ -C₇)cycloalkyl; a (C₃ -C₇)cycloalkylmethyl; ahydroxyl; a (C₁ -C₄)alkoxy; a benzyl; a phenyl; R₂₀ can, in addition,represent a hydrogen or a (C₁ -C₇)alkyl when n is two or three;

or alternatively R₁₉ and R₂₀, together with the nitrogen atom to whichthey are linked, constitute a heterocycle chosen from azetidine,thiomorpholine, perhydroazepine, piperazine and isoxazolidine; R₁₉ andR₂₀, together with the nitrogen to which they are linked, can, inaddition constitute a heterocycle chosen from pyrrolidine, piperidine,morpholine and piperazine substituted at postion 4 with a (C₁ -C₄)alkylwhen n is 2 or 3;

R₂₁ represents a hydrogen or a (C₁ -C₇)alkyl;

R₂₂ represents a hydrogen or a (C₁ -C₇)alkyl;

R₂₃ and R₂₄ each independently represent a hydrogen or a (C₁ -C₇)alkyl;R₂₄ can, in addition, represent a formyl or a (C₁ -C₇)alkylcarbonyl;

R₂₅ represents a hydrogen or a (C₁ -C₇)alkyl;

R₂₆ and R₂₇ each independently represent a hydrogen or a (C₁ -C₇)alkyl;R₂₇ can, in addition, represent a (C₁ -C₇)alkylcarbonyl;

or alternatively R₂₆ and R₂₇, together with the nitrogen atom to whichthey are linked, constitute a heterocycle chosen from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine and perhydroazepine;

R₂₉ represents a (C₁ -C₄)alkoxy; as well as their possible salts withinorganic or organic acids.

The family (Ic) consists of the compounds of formula: ##STR18## inwhich: x, Ar₁, Ar₂, n, A and Z have the meanings given above for (I);

Y has the meaning given above for (Ib);

T represents a --CO-- group; a --CO-- group; a group --CONR₂₈ -- inwhich R₂₈ represents a hydrogen or a (C₁ -C₄)alkyl;

as well as their possible salts with inorganic or organic acids.

More especially, the radical Z can be a phenyl group, which may beunsubstituted or optionally contain one or more substituents.

When Z is a phenyl group, the latter may be monosubstituted ordisubstituted, in particular at positions 2,4, but also, for example, atpositions 2,3 or 4,5 or 3,4 or 3,5; it may also be trisubstituted, inparticular at positions 2,4,6 but also, for example, at 2,3,4 or 2,3,5or 2,4,5 or 3,4,5; tetrasubstituted, for example at 2,3,4,5; orpentasubstituted.

The radical Z can also represent a bicyclic aromatic group such as 1- or2-naphthyl; 1-, 2-, 3-, 4-, 5-, 6- or 7-indenyl, in which one or morebonds may be hydrogenated, it being possible for the said groups to beunsubstituted or optionally to contain one or more substituents such as:an alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, oxo, alkylcarbonylaminoand alkoxycarbonyl, thioalkyl, halogen, alkoxy or trifluoromethyl group,in which groups the alkyls and the alkoxy are C₁ -C₄ groups.

The radical Z can also be a pyridyl, thiadiazolyl, indolyl, indazolyl,imidazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl,benzisoxazolyl, benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyrannyl,thiazolyl, thienyl, furyl, pyrannyl, chromenyl, isobenzofuranyl,pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromannyl orchromannyl group, in which one or more double bonds may be hydrogenated,it being possible for the said groups to be unsubstituted or optionallyto contain one or more substituents such as: an alkyl, phenyl, cyano,hydroxyalkyl, hydroxyl, alkylcarbonylamino and alkoxycarbonyl orthioalkyl group, in which groups the alkyls and the alkoxy are C₁ -C₄groups.

In particular, the invention relates to compounds of formula (I) inwhich:

Z is Z' and represents:

a phenyl unsubstituted or substituted one or more times with asubstituent chosen from: a halogen atom; a trifluoromethyl; a cyano; ahydroxyl; a nitro; an amino unsubstituted or substituted once or twicewith a (C₁ -C₄)alkyl; a benzylamino; a carboxyl; a (C₁ -C₁₀)alkyl; a (C₃-C₈)cycloalkyl unsubstituted or substituted one or more times with amethyl; a (C₁ -C₁₀)alkoxy; a (C₃ -C₈)cycloalkyloxy unsubstituted orsubstituted one or more times with a methyl; a mercapto; a (C₁-C₁₀)alkylthio; a formyloxy; a (C₁ -C₆)alkylcarbonyloxy; a formylamino;a (C₁ -C₆)alkylcarbonylamino; a benzoylamino; a (C₁ -C₄)alkoxycarbonyl;a (C₃ -C₇)cycloalkyloxycarbonyl; a carbamoyl unsubstituted orsubstituted once or twice with a (C₁ -C₄)alkyl; a ureido unsubstitutedor substituted once or twice at position 3 with a (C₁ -C₄)alkyl or a (C₃-C₇)cycloalkyl; a (1-pyrrolidinyl)carbonylamino, the said substituentsbeing identical or different;

a naphthyl unsubstituted or substituted one or more times with ahalogen, a trifluoromethyl, a (C₁ -C₄)alkyl, a hydroxyl, a (C₁-C₄)alkoxy;

a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; animidazolyl.

Furthermore, Z' may also represent a phenyl substituted with a phenylunsubstituted or substituted one or more times with a halogen, atrifluoromethyl, a (C₁ -C₄)alkyl, a hydroxyl, a (C₁ -C₄)alkoxy, the saidsubstituents being identical or different;

In the present description, the alkyl or alkoxy groups are straight orbranched; halogen atom is understood to mean a chlorine, bromine,fluorine or iodine atom.

In the substituents of the group Z=phenyl, (C₁ -C₁₀)alkyl is understoodto mean, for example, a methyl, an ethyl, an n-propyl, an isopropyl, ann-butyl, an isobutyl, a sec-butyl, a tert-butyl, a pentyl or n-pentyl, ahexyl or n-hexyl, a heptyl or an n-heptyl, an octyl or n-octyl, a nonylor n-nonyl, a decyl or an n-decyl; (C₃ -C₈)cycloalkyl optionallysubstituted with a methyl is understood to mean, for example, acyclopropyl, a cyclobutyl, a cyclopentyl, a 1-, 2- or3-methylcyclopentyl, a cyclohexyl, a 1-, 2-, 3- or 4-methylcyclohexyl, acycloheptyl or a cyclooctyl; (C₁ -C₁₀)alkoxy is understood to mean, forexample, a methoxy, an ethoxy, an n-propoxy, an isopropoxy, an n-butoxy,an isobutoxy, a sec-butoxy, a tert-butoxy, a pentyloxy, a hexyloxy, aheptyloxy, an octyloxy, a nonyloxy or a decyloxy; (C₃ -C₈)cycloalkyloxyoptionally substituted with a methyl is understood to mean, for example,a cyclopropyloxy, a cyclobutyloxy, a cyclopentyloxy, a 1-, 2- or3-methylcyclopentyloxy, a cyclohexyloxy, a 1-, 2-, 3- or4-methylcyclohexyloxy, a cycloheptyloxy or a cyclooctyloxy; (C₁-C₁₀)alkylthio is understood to mean, for example, a methylthio, anethylthio, an n-propylthio, an isopropylthio, an n-butylthio, anisobutylthio, a sec-butylthio, a tert-butylthio, a pentylthio, ahexylthio, a heptylthio, an octylthio, a nonylthio or a decylthio; (C₁-C₆)alkylcarbonyloxy is understood to mean, for example, an acetyloxy, apropionyloxy, a butyryloxy, a valeryloxy, a caproyloxy, a heptanoyloxy;a (C₁ -C₆)alkylcarbonyl-amino is understood to mean, for example, anacetylamino, a propionylamino, a butyrylamino, an isobutyrylamino, avalerylamino, a caproylamino or a heptanoylamino; (C₁ -C₄)alkoxycarbonylis understood to mean, for example, a methoxycarbonyl, anethoxycarbonyl, an n-propoxycarbonyl, an isopropoxycarbonyl, ann-butoxycarbonyl, an isobutoxycarbonyl, a sec-butoxycarbonyl or atert-butoxycarbonyl; (C₃ -C₇)cycloalkyloxycarbonyl is understood tomean, for example, a cyclopropyloxycarbonyl, a cyclobutyloxycarbonyl, acyclopentyloxycarbonyl, a cyclohexyloxycarbonyl or acycloheptyloxycarbonyl.

Advantageously, the radical Z represents a phenyl unsubstituted orsubstituted one or more times with a halogen atom, more especially achlorine, fluorine or iodine atom, a trifluoromethyl, a (C₁ -C₄)alkyl, ahydroxyl, a (C₁ -C₄)alkoxy; a naphthyl unsubstituted or substituted oneor more times with a halogen, a trifluoromethyl, a (C₁ -C₄)alkyl, ahydroxyl, a (C₁ -C₄)alkoxy; a pyridyl; a thienyl; an indolyl; aquinolyl; a benzothienyl; an imidazolyl.

According to the present invention, preference is given to the compoundsof formula (I) in which:

x is zero or one;

R₁ represents hydrogen;

R₂ represents a hydrogen or a (C₁ -C₇)alkyl;

or alternatively R₁ and R₂ together constitute a group --(CH₂)_(n)--CQ-- in which Q represents an oxygen atom or two hydrogen atoms and nis one, two or three;

Y represents a group chosen from:

Y₁) (C₁ -C₇)alkyl;

Y₂) --(CH₂)_(p) --OR₃ ;

Y₃) --O--CH₂ CH₂ --OR₄ ;

Y₄) --OCOR₅ ;

Y₅) --(CH₂)_(p) --OCOR₆ ;

Y₆) --CH₂)_(q) --OCONH--(C₁ -C₇)alkyl;

Y₇) --NR₇ R₈ ;

Y₈) --(CH₂)_(p) --NR₉ R₁₀ ;

Y₉) --NR₁₁ COR₁₂ ;

Y₁₀) --(CH₂)_(p) --NR₁₃ COR₁₄ ;

Y₁₁) --(CH₂)_(q) --NR₁₃ COOR₁₅ ;

Y₁₂) --(CH₂)_(q) --NR₁₃ SO₂ R₁₆ ;

Y₁₃) --(CH₂)_(q) --NR₁₃ CONR₁₇ R₁₈ ;

Y₁₄) --CONR₁₀ R₂₀ ;

Y₁₅) --CH₂ --COOR₂₁ ;

Y₁₆) --CH₂ --CONR₁₇ R₁₈ ;

Y₁₇) ##STR19## Y₁₈) ##STR20## Y₁₉) --CO--NR₂₅ --NR₂₆ R₂₇ ; in whichgroups:

p is one or two;

q is zero, one or two;

R₃ represents a (C₁ -C₇)alkyl; R₃ can, in addition, represent hydrogenwhen R₁ and R₂ together constitute a group --(CH₂)_(n) --CQ--;

R₄ represents a hydrogen; a (C₁ -C₇)alkyl; a formyl; a (C₁-C₇)alkylcarbonyl;

R₅ represents a pyridyl or a (C₃ -C₇)cycloalkyl unsubstituted orsubstituted with one or more methyls; R₅ can, in addition, represent aphenyl when R₁ and R₂ together constitute a group --(CH₂)_(n) --CQ--;

R₆ represents hydrogen; a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkylunsubstituted or substituted with one or more methyls; a phenyl; apyridyl;

R₇ represents a hydrogen or a (C₁ -C₇)alkyl;

R₈ represents a (C₃ -C₇)cycloalkylmethyl; a benzyl;

or alternately R₇ and R₈, together with the nitrogen atom to which theyare linked, constitute a heterocycle chosen from: azetidine,thiomorpholine, perhydroazepine, piperazine unsubstituted or substitutedat position 4 with a (C₁ -C₄)alkyl; R₇ and R₈ together with the nitrogenatom to which they are linked can, in addition, constitute a heterocyclechosen from pyrrolidine, piperidine and morpholine when R₁ representshydrogen;

R₉ represents a hydrogen or a (C₁ -C₇)alkyl;

R₁₀ represents a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkylmethyl; a benzyl;R₁₀ can, in addition, represent hydrogen when R₁ and R₂ togetherconstitute a group --(CH₂)_(n) --CQ--;

R₁₁ represents a hydrogen or a (C₁ -C₇)alkyl;

R₁₂ represents a (C₃ -C₇)cycloalkyl unsubstituted or substituted withone or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; athienyl; a pyrrolyl; an imidazolyl; R₁₂ can, in addition, representhydrogen when R₁ represents hydrogen; R₁₂ can, in addition, represent a(C₁ -C₇)alkyl when both R₁₁ represents a (C₁ -C₇)alkyl and R₁ representshydrogen;

or alternatively R₁₁ and R₁₂ together represent a group --(CH₂)_(m) --in which m is three or four;

R₁₃ represents a hydrogen or a (C₁ -C₇)alkyl;

R₁₄ represents a hydrogen; a (C₃ -C₇)cycloalkyl unsubstituted orsubstituted with one or more methyls; a phenyl; a benzyl; a vinyl; apyridyl; a furyl; a thienyl; a pyrrolyl; an imidazolyl; R₁₄ can, inaddition, represent a (C₁ -C₇)alkyl when R₁ and R₂ together constitute agroup --(CH₂)_(n) --CQ--; R₁₄ can, in addition, represent a (C₁-C₇)alkyl when both R₁₃ represents a (C₁ -C₇)alkyl and R₁ representshydrogen;

R₁₅ represents a (C₁ -C₇)alkyl or a phenyl;

R₁₆ represents a (C₁ -C₇)alkyl; an amino, free or substituted with oneor two (C₁ -C₇)alkyls; a phenyl unsubstituted or substituted one or moretimes with a substituent chosen from: a halogen atom, a (C₁ -C₇)alkyl, atrifluoromethyl, a hydroxyl, a (C₁ -C₇)alkoxy, a carboxyl, a (C₁-C₇)alkoxycarbonyl, a (C₁ -C₇)alkylcarbonyloxy, a cyano, a nitro, anamino, free or substituted with one or two (C₁ -C₇)alkyls, the saidsubstituents being identical or different;

R₁₇ and R₁₈ each independently represent a hydrogen or a (C₁ -C₇)alkyl;R₁₈ can, in addition, represent a (C₃ -C₇)cycloalkyl, a (C₃-C₇)cycloalkylmethyl, a hydroxyl, a (C₁ -C₄)alkoxy, a benzyl or aphenyl;

or alternatively R₁₇ and R₁₈, together with the nitrogen atom to whichthey are linked, constitute a heterocycle chosen from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine andpiperazine unsubstituted or substituted at position 4 with a (C₁-C₄)alkyl;

R₁₉ represents a hydrogen or a (C₁ -C₇)alkyl;

R₂₀ represents a (C₃ -C₇)cycloalkyl; a (C₃ -C₇)cycloalkylmethyl; ahydroxyl; a (C₁ -C₄)alkoxy; a benzyl; a phenyl; R₂₀ can, in addition,represent a hydrogen or a (C₁ -C₇)alkyl when R₁ represents hydrogen orwhen R₁ and R₂ together constitute a group --(CH₂)_(n) --CQ-- in which nis two or three.;

or alternatively R₁₉ and R₂₀, together with the nitrogen atom to whichthey are linked, constitute a heterocycle chosen from azetidine,thiomorpholine, perhydroazepine and piperazine; R₁₉ and R₂₀, togetherwith the nitrogen atom to which they are linked, can, in addition,constitute a heterocycle chosen from, pyrrolidine, piperidine,morpholine and piperazine substituted at position 4 with a (C₁ -C₄)alkylwhen R₁ represents hydrogen or when R₁ and R₂ together constitute agroup (CH₂)_(n) --CQ-- in which n is two or three;

R₂₁ represents a hydrogen or a (C₁ -C₇)alkyl;

R₂₂ represents a hydrogen or a (C₁ -C₇)alkyl;

R₂₃ and R₂₄ each independently represent a hydrogen or a (C₁ -C₇)alkyl;R₂₄ can, in addition, represent a formyl or a (C₁ -C₇)alkylcarbonyl;

R₂₅ represents a hydrogen or a (C₁ -C₇)alkyl;

R₂₆ and R₂₇ each independently represent a hydrogen or a (C₁ -C₇)alkyl;

Ar₁ represents a phenyl unsubstituted or substituted one or more timeswith a substituent chosen from: a halogen atom, a hydroxyl, a (C₁-C₄)alkoxy, a (C₁ -C₄)alkyl, a trifluoromethyl, a methylenedioxy, thesaid substituents being identical or different; a thienyl unsubstitutedor substituted with a halogen atom; a benzothienyl unsubstituted orsubstituted with a halogen atom; a naphthyl unsubstituted or substitutedwith a halogen atom; an indolyl unsubstituted or N-substituted with a(C₁ -C₄)alkyl or a benzyl; an imidazolyl unsubstituted or substitutedwith a halogen atom; a pyridyl unsubstituted or substituted with ahalogen atom; a biphenyl;

Ar₂ represents a phenyl unsubstituted or substituted one or more timeswith a substituent chosen from: a halogen atom, a hydroxyl, a (C₁-C₄)alkoxy, a (C₁ -C₄)alkyl, a trifluoromethyl, a methylenedioxy, thesaid substituents being identical or different; a pyridyl; a thienyl; apyrimidyl; an imidazolyl unsubstituted or substituted with a (C₁-C₄)alkyl;

T represents a --CH₂ -- group; a --CO-- group; a --COO-- group; a group--CONR₂₈ -- in which R₂₈ represents a hydrogen or a (C₁ -C₄)alkyl; oncondition that T represents a --CH₂ -- group when Q represents an oxygenatom and T represents one of the groups --CO--, --COO-- or --CONR₂₈ --when Q represents two hydrogen atoms;

A represents a direct bond or a group --(CH₂)_(t) -- in which t is one,two or three;

Z represents an optionally substituted mono-, di- or tricyclic aromaticor heteroaromatic group;

as well as their possible salts with inorganic or organic acids.

The substituent Ar₁ is preferably a phenyl group advantageouslysubstituted with two chlorine atoms or two fluorine atoms, moreespecially in positions 3 and 4.

The substituent Ar2 is preferably an unsubstituted phenyl.

The substituent Y is preferably a group chosen from:

Y₂) --(CH₂)_(p) --OR₃ ;

Y₃) --O--CH₂ CH₂ --OR₄ ;

Y₅) --(CH₂)_(p) --OCOR₆ ;

Y₆) --(CH₂)_(q) --OCONH--(C₁ -C₇)alkyl;

Y₉) --NR₁₁ COR₁₂ ;

Y₁₁) --(CH₂)_(q) --NR₁₃ COOR₁₅ ;

Y₁₂) --(CH₂)_(q) --NR₁₃ SO₂ R₁₆ ;

Y₁₃) --(CH₂)_(q) --NR₁₃ CONR₁₇ R₁₈ ;

Y₁₄) --CONR₁₉ R₂₀ ;

Y₁₅) --CH₂ --COOR₂₁ ;

Y₁₇) ##STR21## Y₁₈) ##STR22## Y₁₉) --CO--NR₂₅ --NR₂₆ R₂₇ ; in whichgroups p, q, R₃, R₄, R₆, R₁₁, R₁₂, R₁₃, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆ and R₂₇ are as defined above for a compoundof formula (I).

A group of preferred compounds according to the present invention arethose of formula: ##STR23## in which: x is as defined above for acompound of formula (I);

R'₂ represents a (C₁ -C₇)alkyl;

Y' represents a group chosen from:

Y₃) --O--CH₂ CH₂ --OR₄ ;

Y₆) --(CH₂)_(q) --OCONH--(C₁ -C₇)alkyl;

Y₉) --NR₁₁ COR₁₂ ;

Y₁₁) --(CH₂)_(q) --NR₁₃ COOR₁ ₁₅ ;

Y₁₂) --(CH₂)_(q) --NR₁₃ SO₂ R₁₆ ;

Y₁₃) --(CH₂)_(q) --NR₁₃ CONR₁₇ R₁₈ ;

Y₁₄) --CONR₁₉ R₂₀ ;

Y₁₅) --CH₂ --COOR₂₁ ;

Y₁₇) ##STR24## Y₁₈) ##STR25## Y₁₉) --CO--NR₂₅ --NR₂₆ R₂₇ ; in whichgroups q, R₄, R₁₁, R₁₂, R₁₃, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,R₂₃, R₂₄, R₂₅, R₂₆ and R₂₇ are as defined for a compound of formula(Ia);

Ar'₁ represents a phenyl unsubstituted or substituted one or more timeswith a substituent chosen from: a halogen atom, a hydroxyl, a (C₁-C₄)alkoxy, a (C₁ -C₄)alkyl, a trifluoromethyl, a methylenedioxy, thesaid substituents being identical or different;

Ar'₂ represents a phenyl unsubstituted or substituted one or more timeswith a substituent chosen from: a halogen atom, a hydroxyl, a (C₁-C₄)alkoxy, a (C₁ -C₄)alkyl, a trifluoromethyl, a methylenedioxy, thesaid substituents being identical or different;

A' represents a direct bond or a --CH₂ -- group;

Z' is as defined above;

and their salts with inorganic or organic acids.

Among these compounds, those of formula: ##STR26## in which: x, Y' andA' are as defined for a compound of formula (I'a);

Ar"₁ represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl;

Ar"₂ represents an unsubstituted phenyl;

Z'a represents an unsubstituted phenyl or a phenyl substituted atposition 3 with a halogen or a (C₁ -C₁₀)alkoxy;

and their salts with inorganic or organic acids, are especiallypreferred.

Among these compounds, those of formula: ##STR27## in which: A' is asdefined for a compound of formula (I'a);

Z'a is as defined for a compound of formula (I"a);

q, R₁₃, R₁₇ and R₁₈ are as defined for a compound of formula (Ia);

and their salts with inorganic or organic acids, are most especiallypreferred.

The compounds of formula (I'"a) in optically pure form, and their saltswith inorganic or organic acids, are more especially preferred.

Another group of preferred compounds according to the invention arethose of formula: ##STR28## in which: n and x are as defined above for acompound of formula (I);

Ar'₁, Ar'₂ and Z' are as defined above for a compound of formula (I'a);

Y" represents a group chosen from:

Y₃) --O--CH₂ CH₂ --OR₄ ;

Y₆) --(CH₂)_(q) --OCONH--(C₁ -C₇)alkyl;

Y₉) --NR₁₁ COR₁₂ ;

Y₁₁) --(CH₂)_(q) --NR₁₃ COOR₁₅ ;

Y₁₂) --(CH₂)_(q) --NR₁₃ SO₂ R₁₆ ;

Y₁₃) --(CH₂)_(q) --NR₁₃ CONR₁₇ R₁₈ ;

Y₁₄) --CONR₁₉ R₂₀ ;

Y₁₅) --CH₂ --COOR₂₁ ;

Y₁₇) ##STR29## Y₁₈) ##STR30## Y₁₉) --CO--NR₂₅ --NR₂₆ R₂₇ ; in whichgroups q, R₄, R₁₁, R₁₂, R₁₃, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,R₂₃, R₂₄, R₂₅, R₂₆ and R₂₇ are as defined for a compound of formula(Ib);

and their salts with inorganic or organic acids.

Among these compounds, those of formula: ##STR31## in which: x and Y"are as defined for a compound of formula (I'b);

Ar"₁ and Ar"₂ are as defined for a compound of formula (I"a)

Z'b represents an unsubstituted phenyl, a3,5-bis(trifluoromethyl)phenyl, a 3,5-dimethylphenyl or a2,4-bis(trifluoromethyl)phenyl;

and their salts with inorganic or organic acids, are especiallypreferred.

Among these compounds, those of formula: ##STR32## in which: Z'b is asdefined for a compound of formula (I"b);

q, R₁₃, R₁₇ and R₁₈ are as defined for a compound of formula (Ib);

and their salts with inorganic or organic acids, are most especiallypreferred.

The compounds of formula (I'"b) in optically pure form, and their saltswith inorganic or organic acids, are more especially preferred.

Another group of preferred compounds according to the invention arethose of formula: ##STR33## in which: x and n are as defined for acompound of formula (I);

Ar'₁, Ar'₂ and Z' are as defined for a compound of formula (I'a);

Y" is as defined for a compound of formula (I'b);

and their salts with inorganic or organic acids.

Among these compounds, those of formula: ##STR34## in which: x and Y"are as defined for a compound of formula (I'c);

Ar"₁ and Ar"₂ are as defined for a compound of formula (I"a);

Z'c represents a phenyl substituted at position 3 with a halogen or a(C₁ -C₁₀)alkoxy group; and their salts with inorganic or organic acids,are especially preferred.

According to another of its aspects, the present invention relates tothe obtaining of the compounds of formula (I) of and their salts.

One of the processes according to the invention for obtaining thecompounds (process A) is suitable for the preparation of the compoundsof formula (I) in which R₁ and R₂ together constitute a group--(CH₂)_(n) --CQ-- in which Q represents an oxygen atom and n is one,two or three [compounds of formula (Ib)].

This process is characterized in that:

1) a compound of formula: ##STR35## in which n and Ar₁ are as definedfor a compound of formula (I) and E represents hydrogen or anO-protecting group, is treated with a halogenated derivative of formula:

    Hal--CH.sub.2 --A--Z                                       (III)

in which Hal represents a halogen atom, preferably bromine, and A and Zare as defined above for a compound of formula (I), to obtain a compoundof formula: ##STR36## 2) the O-protecting group is, where appropriate,removed by the action of an acid or a base, to obtain the alcohol offormula: ##STR37## 3) the alcohol (V) is treated with a compound offormula:

    G--SO.sub.2 --Cl                                           (VI)

in which G represents a methyl, phenyl, tolyl or trifluoromethyl group,to obtain a compound of formula: ##STR38## 4) the compound (VII) isreacted with a piperidine of formula: ##STR39## in which x and Ar₂ areas defined for a compound of formula (I) and Y.sub.α represents either Yas defined for (I) or a precursor of Y, on the understanding that, whenY.sub.α contains a hydroxyl group or an amino group, these groups may beprotected;

5) and, after deprotection, where appropriate, of the hydroxyl groups orthe amino groups, or conversion, where appropriate, of Y.sub.α to Y, theproduct thereby obtained is optionally converted to one of its saltswith an inorganic or organic acid.

Another process according to the invention for obtaining the compounds(process B) is suitable for the preparation of the compounds of formula(I) in which R₁ and R₂ together constitute a group --(CH₂)_(n) --CQ-- inwhich Q represents two hydrogen atoms and n is one, two or three(compounds of formula [(Ic)], or the compounds of formula (I) in whichR₁ represents hydrogen [compounds of formula (Ia)].

This process is characterized in that:

1) a compound of formula: ##STR40## in which Ar₁ is as defined for acompound of formula (I), R'₁ represents hydrogen and R'₂ represents ahydrogen or a (C₁ -C₇)alkyl, or alternatively R'₁ and R'₂ togetherconstitute a group --(CH₂)_(n) --CQ-- in which Q represents two hydrogenatoms and n is one, two or three, and E represents hydrogen or anO-protecting group, is treated

either with a halogenated derivative of formula:

    Hal--CH.sub.2 --A--Z                                       (III)

in which Hal represents a halogen atom, preferably bromine, and A and Zare as defined for a compound of formula (I), when R₁ representshydrogen and R₂ represents hydrogen or a (C₁ -C₇)alkyl, when a compoundof formula (Ia) is to be prepared in which T is --CH₂ --;

or with a functional derivative of an acid of formula:

    HO--CO--A--Z                                               (IIIa)

in which A and Z are as defined above, when a compound of formula (I) isto be prepared in which T is --CO--;

or with a chloroformate of formula:

    CI--COO--A--Z                                              (IIIb)

in which A and Z are as defined above, when a compound of formula (I) isto be prepared in which T is --COO--;

or with an isocyanate of formula:

    O═C═N--A--Z                                        (IIIc)

in which A and Z are as defined above, when a compound of formula (I) isto be prepared in which T is a group --CO--NR₂₈ -- in which R₂₈represents hydrogen;

or with a carbamoyl chloride of formula: ##STR41## in which A and Z areas defined above and R'₂₈ represents a (C₁ -C₄)alkyl, when a compound offormula (I) is to be prepared in which T is --CONR₂₈ -- in which R₂₈ isa (C₁ -C₄)alkyl;

to obtain a compound of formula: ##STR42## 2) where appropriate, whenR'₂ represents hydrogen, and on condition that T is other than--CO--NH-- or that --T--A-- is other than --CO--(CH₂)_(t) --, analkylation reaction is performed to obtain a compound of formula (X) inwhich R'₂ represents a (C₁ -C₇)alkyl;

3) the O-protecting group is, where appropriate, removed from thecompound obtained in step 1) or in step 2) by the action of an acid or abase, to obtain the alcohol of formula: ##STR43## 4) the alcohol (XI) istreated with a compound of formula:

    G--SO.sub.2 --Cl                                           (VI)

in which G represents a methyl, phenyl, tolyl or trifluoromethyl group,to obtain a compound of formula: ##STR44## 5) the compound (XII) isreacted with a piperidine of formula (VIII) as defined above;

6) and, after deprotection, where appropriate, of the hydroxyl groups orthe amino groups, or conversion, where appropriate, of Y.sub.α to Y, theproduct thereby obtained is optionally converted to one of its saltswith an inorganic or organic acid.

During any one of the steps of the processes A or B for preparing thecompounds of formula (I), and more especially when compounds of formula(VIII) or intermediate compounds of formula (II) or (IX) are employed,it may be necessary and/or desirable to protect the reactive orsensitive functional groups, such as the amine, hydroxyl or carboxylgroups, present on any one of the molecules in question. This protectionmay be performed using conventional protective groups, such as the onesdescribed in Protective Groups in Organic Chemistry, J. F. W. McOmie,Ed. Plenum Press, 1973 and in Protective Groups in Organic Synthesis, T.W. Greene and P. G. M. Wutts, Ed. John Wiley and Sons, 1991. Removal ofthe protective groups may take place in an opportune subsequent stepusing methods known to a person skilled in the art which do not affectthe remainder of the molecule in question.

Thus, in process A or in process B, when E represents an O-protectinggroup, the latter is chosen from the traditional O-protecting groupswell known to a person skilled in the art, such as, for example,tetrahydro-2-pyranyl, benzoyl or a (C₁ -C₄)alkylcarbonyl.

The O-protecting groups used, where appropriate, to obtain a compound offormula (I) in which Y contains a hydroxyl are the traditionalO-protecting groups well known to a person skilled in the art, asdefined above for E.

The N-protecting groups used, where appropriate, to obtain a compound offormula (I) in which Y contains an amino group are the traditionalN-protecting groups well known to a person skilled in the art, such as,for example, the trityl, methoxytrityl, tert-butoxycarbonyl orbenzyloxycarbonyl group.

In step 1) of process A or in step 1) of process B, when a halogenatedderivative of formula (III) is used, the reaction is performed in aninert solvent such as tetrahydrofuran, N,N-dimethylformamide or dimethylsulphoxide in the presence of a base such as potassium tert-butylate,sodium hydride or lithium diisopropylamide and at a temperature ofbetween 0° C. and 80° C.

In step 1) of process B, as a functional derivative of the acid (IIIa),the acid itself is used, or alternatively one of the functionalderivatives which react with amines, for example an anhydride, a mixedanhydride, the acid chloride or an activated ester such as thepara-nitrophenyl ester.

When the acid of formula (IIIa) itself is employed, the reaction iscarried out in the presence of a coupling agent used in peptidechemistry, such as 1,3-dicyclohexylcarbodiimide orbenzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate,in the presence of a base such as triethylamine orN,N-diisopropylethylamine, in an inert solvent such as dichloromethaneor N,N-dimethylformamide at a temperature between 0° C. and roomtemperature.

When an acid chloride is used, the reaction is performed in an inertsolvent such as dichloromethane or benzene, in the presence of a basesuch as triethylamine or N-methylmorpholine and at a temperature between-60° C. and room temperature.

When a chloroformate of formula (IIIb) is used, the reaction isperformed in an inert solvent such as dichloromethane, at a temperaturebetween 0° C. and room temperature and in the presence of a base such astriethylamine.

When an isocyanate of formula (IIIc) is used, the reaction is performedin an inert solvent such as dichloromethane or benzene at roomtemperature.

When a carbamoyl chloride of formula (IIId) is used, the reaction isperformed in a solvent such as toluene or 1,2-dichloroethane, at atemperature of between 0° C. and 110° C. and in the presence of a basesuch as triethylamine.

In step 2) of process B, where appropriate, a compound of formula (X) inwhich R'₂ represents hydrogen is subjected to a subsequent treatment toprepare a compound of formula (X) in which R'₂ represents a (C₁-C₇)alkyl. The alkylation reaction is performed by the action of a C₁-C₇ alkyl halide or sulphate, in the presence of a base such as sodiumhydride, in an inert solvent such as tetrahydrofuran,N,N-dimethylformamide or toluene, at a temperature between 0° C. androom temperature.

In step 2) of process A or in step 3) of process B, where appropriate,the compound of formula (IV) or the compound or formula (X) therebyobtained is deprotected according to methods known to a person skilledin the art. For example, when E represents a tetrahydro-2-pyranyl group,the deprotection is performed by acid hydrolysis using hydrochloric acidin a solvent such as ether, methanol or a mixture of these solvents, orusing pyridinium p-toluenesulphonate in a solvent such as methanol, oralternatively using an Amberlyst® resin in a solvent such as methanol.The reaction is performed at a temperature between room temperature andrefluxing temperature of the solvent. When E represents a benzoyl groupor a (C₁ -C₄)alkylcarbonyl group, deprotection is performed byhydrolysis in an alkaline medium using, for example, an alkali metalhydroxide such as sodium hydroxide, potassium hydroxide or lithiumhydroxide, in an inert solvent such as water, methanol, ethanol, dioxaneor a mixture of these solvents, at a temperature of between 0° C. andthe refluxing temperature of the solvent.

In step 3) of process A according to step 4) of process B, the reactionof the alcohol of formula (V) or of the alcohol of formula (XI) with asulphonyl chloride of formula (VI) is performed in the presence of abase such as triethylamine, pyridine, N,N-diisopropylethylamine orN-methylmorpholine, in an inert solvent such as dichloromethane, benzeneor toluene and at a temperature between -20° C. and the refluxingtemperature of the solvent.

In step 4) of process A or in step 5) of process B, the compound (VII)or the compound (XII) thereby obtained is reacted with a piperidine offormula (VIII). The reaction is performed in an inert solvent such asN,N-dimethylformamide, acetonitrile, methylene chloride, toluene orisopropanol and in the presence or absence of a base. When a base isused, the latter is chosen from organic bases such as triethylamine,N,N-diisopropylethylamine and N-methylmorpholine, or from alkali metalcarbonates or bicarbonates such as potassium carbonate, sodium carbonateand sodium bicarbonate. In the absence of base, the reaction isperformed using an excess of the compound of formula (VIII) andoptionally in the presence of an alkali metal iodide such as potassiumiodide or sodium iodide. The reaction is performed at a temperaturebetween room temperature and 100° C.

Finally, after deprotection, where appropriate, of the hydroxyl groupsor the amino groups, or conversion, where appropriate, of Y.sub.α to Y,the compounds of formula (I) according to the invention are obtained.

The compounds of formula (I) are isolated in free base or salt formaccording to traditional techniques.

Thus, when the compound of formula (I) is obtained in free base form,salification is performed by treatment with the chosen acid in anorganic solvent. By treatment of the free base, dissolved, for example,in an ether such as diethyl ether or in an alcohol such as 2-propanol orin acetone or in dichloromethane or in ethyl acetate, with a solution ofthe chosen acid in the same solvent, the corresponding salt is obtainedand is isolated according to traditional techniques.

Thus, the hydrochloride, hydrobromide, sulphate, hydrogen sulphate,dihydrogen phosphate, methane sulphonate, oxalate, maleate, fumarate,2-naphthalenesulphonate or benzenesulphonate is, for example, prepared.

At the end of the reaction, the compounds of formula (I) may be isolatedin the form of one of their salts, for example the hydrochloride or theoxalate; in this case, if necessary, the free base may be prepared byneutralization of the said salt with an inorganic or organic base suchas sodium hydroxide or triethylamine or with an alkali metal carbonateor bicarbonate such as sodium or potassium carbonate or bicarbonate.

The compounds of formula (II) are obtained by known methods, especiallythe ones which are described in Patent Application EP-A-0512901.

In particular, a compound of formula (II) in which n=2 may be preparedaccording to Scheme 1 below. ##STR45##

In step 1 of SCHEME 1, a compound of formula (XIII) is reacted with acompound of formula (XIV) according to the method described in PatentApplications EP-A-0428434 and EP-A-0474561.

In step 2, the reaction of the compound of formula (XV) thereby obtainedwith methyl acrylate in the presence of a base such as Triton® B or1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) enables the compound offormula (XVI) to be obtained.

In step 3, the compound of formula (XVI) is subjected to a hydrogenationin the presence of a catalyst such as Raney® nickel, to obtain thecompound of formula (II) in which n=2.

The compounds of formula (IX) are obtained by known methods, especiallythe ones which are described in Patent Applications EP-A-0428434,EP-A-0474561, EP-A-0512901 and EP-A-591040.

The compounds of formula (III), (IIa), (IIIb), (IIIc) or (IIId) areknown, or prepared by known methods.

The piperidines of formula (VIII) are known, or are prepared by knownmethods such as the ones described in the following publications:

J. Org. Chem., 1957, 22, 1484-1489;

J. Heterocyclic Chem., 1986, 23, 73-75;

J. Chem. Soc., 1945, 917;

J. Pharmaceutical Sci., 1972, 61 (8), 1316-1317;

Chem. Ber., 1975, 108, 3475-3482.

The compounds of formula (VIII) are generally prepared in a formprotected on the piperidine nitrogen; after a deprotection step, thecompounds of formula (VIII) themselves are obtained.

More especially, a compound of formula (VIII) in which Y.sub.αrepresents a group --(CH₂)_(p) --OR₃ in which R₃ represents hydrogen andp is one or two, respectively, is, for example, prepared by reduction ofa compound of formula (VIII) in which Y.sub.α represents amethoxycarbonyl or a methoxycarbonylmethyl, respectively, according tothe method described in Chem. Ber., 1975, 108, 3475-3482.

A compound of formula (VIII) in which Y.sub.α represents a group--(CH₂)_(p) --OR₃ in which R₃ represents a (C₁ -C₇)alkyl is prepared byalkylation of a compound of formula (VIII) in which Y.sub.α represents agroup --(CH₂)_(p) --OH according to methods known to a person skilled inthe art.

A compound of formula (VIII) in which Y.sub.α represents a group--O--CH₂ --CH₂ --OR₄ in which R₄ represents hydrogen is prepared byreaction of a compound of formula (VIII) in which Y.sub.α represents abenzoyloxy with ethylene glycol in the presence of an acid such assulphuric acid.

By an identical reaction, and using a 2--(C₁ -C₇)alkoxyethanol, thecompounds of formula (VIII) are prepared in which Y.sub.α represents agroup --O--CH₂ CH₂ --OR₄ in which R₄ represents a (C₁ -C₇)alkyl.

By the action of formic acid on a compound of formula (VIII) in whichY.sub.α represents an --O--CH₂ CH₂ --OH group, the compounds of formula(VIII) are prepared in which Y.sub.α represents a group --O--CH₂ CH₂--OR₄ in which R₄ represents a formyl. By the action of a C₂ -C₈ acidchloride, and in the presence of a base such as triethylamine, thecompounds of formula (VIII) are prepared in which Y.sub.α represents agroup -0--CH₂ CH₂ --OR₄ in which R₄ represents a (C₁ -C₇)alkylcarbonyl.

A compound of formula (VIII) in which Y.sub.α represents a group --OCOR₅is prepared by reaction of an acid chloride R₅ COCl on a compound offormula (VIII) in which Y.sub.α represents a hydroxyl, and in thepresence of a base such as triethylamine.

Similarly, by the action of an acid chloride R₆ COCl (R₆ other thanhydrogen) on a compound of formula (VIII) in which Y.sub.α represents agroup --(CH₂)_(p) --OH, the compounds of formula (VIII) are prepared inwhich Y.sub.α represents a group --(CH₂)_(p) --OCOR₆ (R₆ other thanhydrogen).

By the action of formic acid on a compound of formula (VIII) in whichY.sub.α represents a group --(CH₂)_(p) --OH, the compounds of formula(VIII) are prepared in which Y.sub.α represents a group --(CH₂)_(p)--OCOR₆ in which R₆ represents hydrogen.

By the action of a carbamoyl chloride (C₁ -C₇)alkyl-NHCOCl on thecompounds of formula (VIII) in which Y.sub.α represents a group--(CH₂)_(q) --OH, the compounds of formula (VIII) are obtained in whichY.sub.α represents a group --(CH₂)_(q) --OCONH--(C₁ -C₇)alkyl. The samecompounds are prepared by the action of an isocyanate (C₁-C₇)alkyl-N═C═O on the compounds of formula (VIII) in which Y.sub.αrepresents a group --(CH₂)_(q) --OH.

To prepare a compound of formula (VIII) in which Y.sub.α represents agroup --NR₇ R₈ in which R₇ represents hydrogen and R₈ represents a (C₃-C₇)cycloalkylmethyl or a benzyl, respectively, it is possible toperform a reduction of a compound of formula (VIII) in which Y.sub.αrepresents a group --NR₁₁ COR₁₂ in which R₁₃ represents hydrogen and R₁₂represents a (C₃ -C₇)cycloalkyl or a phenyl, respectively. The reactionis performed by means of a reducing agent such as lithium aluminiumhydride in a solvent such as tetrahydrofuran at the refluxingtemperature of the solvent.

By an identical reaction, the compounds of formula (VIII) in whichY.sub.α represents a group --NR₇ R₈ in which R₇ represents a (C₁-C₇)alkyl may be prepared from the compounds of formula (VIII) in whichY.sub.α represents a group --NR₁₁ COR₁₂ in which R₁₁ represents a (C₁-C₇)alkyl.

A compound of formula (VIII) in which Y.sub.α represents a group --NR₇R₈ in which R₇ and R₈, together with the nitrogen atom to which they arelinked, constitute a heterocycle is prepared by application oradaptation of the Bruylants reaction (Bull. Soc. Chim. Belges, 1924, 33,467 and Tetrahedron Letters, 1988, 29 (52), 6827-6830).

To prepare a compound of formula (VIII) in which Y.sub.α represents agroup --CH₂ --NR₉ R₁₀ in which R₉ and R₁₀ each represent hydrogen, thereduction is performed with a compound of formula (VIII) in whichY.sub.α represents a cyano. This reduction is performed according tomethods well known to a person skilled in the art.

A compound of formula (VIII) in which Y.sub.α represents a group --CH₂--CH₂ --NR₉ R₁₀ in which R₉ and R₁₀ each represent a hydrogen isprepared from a compound of formula (VIII) in which Y.sub.α represents a--CH₂ --CH₂ --OH group, by application or adaptation of the methoddescribed in J. Med. Chem., 1989, 32, 391-396.

The compounds of formula (VIII) in which Y.sub.α represents a group--(CH₂)_(p) --NR₉ R₁₀ in which R₉ represents a hydrogen or a (C₁-C₇)alkyl and R₁₀ represents a (C₁ -C₇)alkyl, a (C₃-C₇)cycloalkyltnethyl or a benzyl may be prepared by reduction of acompound of formula (VIII) in which Y.sub.α represents a group--(CH₂)_(p) --NR₁₃ COR₁₄ in which R₁₃ represents a hydrogen or a (C₁-C₇)alkyl and R₁₄ represents a (C₁ -C₆)alkyl, a (C₃ -C₇)cycloalkyl or aphenyl.

The compounds of formula (VIII) in which Y.sub.α represents a group--NR₁₁ COR₁₂ in which R₁₁ represents a hydrogen or a (C₁ -C₇)alkyl andR₁₂ represents hydrogen or a (C₁ -C₇)alkyl, a (C₃ -C₇)cycloalkyl, aphenyl, a benzyl, a vinyl, a pyridyl, a furyl, a thienyl, a pyrrolyl oran imidazolyl, respectively, are obtained by the action of formic acidin acetic anhydride or of a suitable acid chloride R₁₂ COCl,respectively, in the presence of a base such as triethylamine, on acompound of formula (VIII) in which Y.sub.α represents a group --NHR₁₁.In particular, a compound of formula (VIII) in which Y.sub.α representsa group --NR₁₁ COR₁₂ in which R₁₂ represents an ethyl radical may beprepared by hydrogenation, in the presence of a catalyst such aspalladium on charcoal, of a compound of formula (VIII) in which Y.sub.αrepresents an acryloylamino or acryloyl--N--(C₁ -C₇)alkylamino group.

A compound of formula (VIII) in which Y.sub.α represents a group --NR₁₁COR₁₂ in which R₁₁ and R₁₂ together represent a --(CH₂)₃ -- or --(CH₂)₄-- group is prepared by application or adaptation of the methoddescribed in J. Med. Chem., 1985, 28, 46-50.

To prepare a compound of formula (VIII) in which Y.sub.α represents anamino group, a hydrolysis of a compound of formula (VIII) in whichY.sub.α represents an acetamido group is performed in an acid medium.

The compounds of formula (VIII) in which Y.sub.α represents a group--(CH₂)_(p) --NR₁₃ COR₁₄ in which p is 1 or 2, R₁₃ represents a hydrogenor a (C₁ -C₇)alkyl and R₁₄ represents a hydrogen or a (C₁ -C₇)alkyl, aphenyl, a benzyl, a pyridyl an optionally substituted (C₃-C₇)cycloalkyl, a vinyl, a furyl, a thienyl, a pyrrolyl or animidazolyl, respectively, are obtained by the action of formic acid inacetic anhydride or of a suitable acid chloride R₁₄ COCl, respectively,in the presence of a base such as triethylamine, on a compound offormula (VIII) in which Y.sub.α represents a group --CH₂ --NHR₁₃ or--CH₂ --CH₂ --NHR₁₃.

By the action of a chloroformate of formula ClCOOR₁₅ on a compound offormula (VIII) in which Y.sub.α represents a group --(CH₂)_(q) --NHR₁₃,in the presence of a base such as triethylamine, a compound of formula(VIII) is prepared in which Y.sub.α represents a group --(CH₂)_(q)--NR₁₃ COOR₁₅.

It is also possible to prepare a compound of formula (VIII) in whichY.sub.α represents a group --(CH₂)_(q) --NR₁₃ COOR₁₅ in which q=0 andR₁₃ represents hydrogen by the action of a compound R₁₅ OH with acompound of formula (VIII) in which Y.sub.α represents an isocyanatogroup (--N═C═O).

A compound of formula (VIII) in which Y.sub.α represents an isocyanatogroup is prepared from a compound of formula (VIII) in which Y.sub.αrepresents a carboxyl according to the method described in OrganicSynthesis, 51, 48-52.

By the action of a sulphonyl chloride ClSO₂ R₁₆ on a compound of formula(VIII) in which Y.sub.α represents a group --(CH₂)_(q) --NHR₁₃, in thepresence of a base such as triethylamine, a compound of formula (VIII)is prepared in which Y.sub.α represents a group --(CH₂)_(q) --NR₁₃ SO₂R₁₆.

Similarly, by the action of an isocyanate of formula R₁₈ N═C═O in whichR₁₈ represents a (C₁ -C₇)alkyl, the compounds of formula (VIII) areprepared in which Y.sub.α represents a group --(CH₂)_(q) --NR₁₃ CONR₁₇R₁₈ in which R₁₇ represents a hydrogen and R₁₈ represents a (C₁-C₇)alkyl.

By the action of a carbamoyl chloride of formula ClCONR₁₇ R₁₈, thecompounds of formula (VIII) are prepared in which Y.sub.α represents agroup --(CH₂)_(q) --NR₁₃ CONR₁₇ R₁₈ in which R₁₇ represents a (C₁-C₇)alkyl and R₁₈ represents a (C₁ -C₇)alkyl or a cycloalkyl.

It is also possible to obtain a compound of formula (VIII) in whichY.sub.α represents a group --(CH₂)_(q) --NR₁₃ CONR₁₇ R₁₈ a by the actionof a compound HNR₁₇ R₁₈ in which R₁₇ and R₁₈ are as defined for thecompounds of formula (I), with a compound of formula (VIII) in whichY.sub.α represents a group --(CH₂)_(q) --NR₁₃ COOR₁₅ in which R₁₅represents a phenyl.

A compound of formula (VIII) in which Y.sub.α represents a group--CH₂)_(q) --NR₁₃ CONR₁₇ R₁₈ in which q=0 and R₁₃ represents hydrogenmay also be prepared by the action of a compound NHR₁₇ R₁₈ with acompound of formula (VIII) in which Y.sub.α represents an isocyanatogroup.

To prepare a compound of formula (VIII) in which Y.sub.α represents agroup --CONR₁₉ R₂₀, a compound of formula (VIII) in which Y.sub.αrepresents a carboxyl is reacted with a compound of formula HNR₁₉ R₂₀according to methods well known to a person skilled in the art.

Similarly, the compounds of formula (VIII) in which Y.sub.α represents agroup --CH₂ --CONR₁₇ R₁₈, are prepared by reaction of a compound offormula (VIII) in which Y.sub.α represents a group --CH₂ --COOR₂₁ inwhich R₂₁ represents hydrogen with a compound HNR₁₇ R₁₈.

A compound of formula (VIII) in which Y.sub.α represents a carboxyl maybe prepared by hydrolysis of a compound of formula (VIII) in whichY.sub.α represents a cyano, according to methods known to a personskilled in the art.

A compound of formula (VIII) in which Y.sub.α represents a carboxymethylmay be prepared according to the method described in Chem. Ber., 1975,108, 3475-3482.

A compound of formula (VIII) in which Y.sub.α represents a (C₁-C₇)alkoxycarbonyl or a (C₁ -C₇)alkoxycarbonylmethyl, respectively, maybe prepared from a compound of formula (VIII) in which Y.sub.αrepresents a carboxyl or a carboxymethyl, respectively, by anesterification reaction according to methods well known to a personskilled in the art.

To prepare a compound of formula (VIII) in which Ar₂ represents anoptionally substituted phenyl radical, x is one and Y.sub.α represents a(C₁ -C₇)alkoxycarbonyl, a protected 4-(C₁ -C₇)alkoxycarbonylpiperidineis reacted with an optionally substituted benzyl halide in the presenceof a base such as sodium hydride, potassium tert-butylate or sodiumdiisopropylamide in a solvent such as tetrahydrofuran,N,N-dimethylformamide or dimethyl sulphoxide, at a temperature between-78° C. and room temperature. After a deprotection step, the expectedcompound of formula (VIII) is obtained.

To prepare a compound of formula (VIII) in which Y.sub.α represents agroup ##STR46## in which R₂₃ and R₂₄ each independently represent ahydrogen or a (C₁ -C₇)alkyl, a compound of formula (VIII) in whichY.sub.α represents a group ##STR47## in which Hal represents a halogenatom, preferably bromine, is reacted with a thiourea in which one of theamino groups is free or substituted with one or two (C₁ -C₇)alkyls.

A compound of formula (VIII) in which Y.sub.α represents a group##STR48## in which R₂₄ represents a formyl or a (C₁ -C₇)alkylcarbonyl,respectively, is prepared by reaction of formic acid in acetic anhydrideor of an acid chloride (C₁ -C₇)alkyl-COCl, respectively, in the presenceof a base such as triethylamine, with the compound of formula (VIII)above protected on the piperidine nitrogen, and in which R₂₄ representshydrogen. After a deprotection step, the expected compound is obtained.

The compound of formula (VIII) in which Y.sub.α represents a group##STR49## in which Hal represents a bromine atom is obtained bybromination according to traditional methods of a compound of formula(VIII) in which Y.sub.α represents a group --CO--CH₂ R₂₂.

A compound of formula (VIII) in which Y.sub.α represents a group##STR50## may be prepared by reaction of a protected compound of formula(VIII) in which Y.sub.α represents a carbazoyl group (--CONH--NH₂) withcyanogen bromide according to the method described in J. Org. Chem.,1961, 26, 88-95. The compound of formula (VIII) in which Y.sub.αrepresents a carbazoyl group is obtained by reaction of hydrazine with acompound of formula (VIII) in which Y.sub.α represents a chloroformyl,which is itself obtained by reaction of thionyl chloride with a compoundof formula (VIII) in which Y.sub.α represents a carboxyl.

A compound of formula (VIII) in which Y.sub.α represents a group--CO--NR₂₅ --NR₂₆ R₂₇ is prepared by reaction of a hydrazine HNR₂₅--NR₂₆ R₂₇ with a compound of formula (VIII) in which Y.sub.α representsa chloroformyl.

A compound of formula (VIII) in which Y.sub.α represents a group --NR₁₁C(═W₁)R₁₂ or a group --(CH₂)_(p) --NR₁₃ C(═W₁)R₁₄ in which groups W₁represents a sulphur atom is prepared from a corresponding compound offormula (VIII) protected on the piperidine nitrogen, and in which W₁represents an oxygen atom by reaction with phosphorus pentasulphide orwith Lawesson's reagent,2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide,followed by deprotection of the piperidine nitrogen.

By reaction of a compound of formula (VIII), protected on the piperidinenitrogen, in which Y.sub.α represents a group --(CH₂)_(q) --NR₁₃ CONR₁₇R₁₈ with phosphorus pentasulphide or with Lawesson's reagent, a compoundof formula (VIII) is prepared in which Y.sub.α represents a group--CH₂)_(q) --NR₁₃ C(═W₁)NR₁₇ R₁₈ in which W₁ is a sulphur atom.

According to the methods mentioned above, a compound of formula (VIII)in which Y.sub.α represents a group --C(═W₁)NR₁₉ R₂₀ or a group --CH₂--C(═W₁)NR₁₇ R₁₈ in which groups W₁ represents a sulphur atom isprepared from a corresponding compound of formula (VIII) in which W₁represents an oxygen atom.

A compound of formula (VIII) in which Y.sub.α represents a group --NR₂₅COCOR₂₉ in which R₂₉ represents a (C₁ -C₄)alkoxy is prepared by reactionof a compound of formula Cl-COCOR₂₉ with a compound of formula (VIII) inwhich Y.sub.α represents an --NHR₂₅ group.

A compound of formula (VIII) in which Y.sub.α represents a group:##STR51## is prepared by heating a protected compound of formula (VIII)in which Y.sub.α represents a --CONH--NH--CO--CH₃ group in the presenceof p-toluenesulphonic acid.

The enantiomers of the compounds according to the invention, of formula:##STR52## in which: "*" means that the carbon atom thus labelled has theparticular (+) or (-) absolute configuration;

x, R₁, R₂, Y, Ar₁, Ar₂, T, A and Z are as defined for the compounds offormula (I);

as well as their salts with inorganic or organic acids;

are new compounds which form part of the invention.

The resolution of the racemic mixtures of the compounds of formula (I)enables the enantiomers of formula (I*) to be isolated. It is, however,preferable to perform the resolution of the racemic mixtures from anintermediate compound which is useful for the preparation of a compoundof formula (I), as described in Patent Applications: EP-A-0474561,EP-A-0512901, EP-A-0612716 and EP-A-0591040.

The compounds of formula (I) above also comprise those in which one ormore hydrogen, carbon or iodine atoms have been replaced by theirradioactive isotope, for example tritium, carbon-14 or iodine-125. Suchlabelled compounds are useful in research, metabolic or pharmacokineticwork, in biochemical tests as receptor ligands.

The affinity of the compounds for the tachykinin receptors was evaluatedin vitro by several biochemical tests using radioligands:

1) The binding of [¹²⁵ I]BH-SP (substance P labelled with iodine-125using the Bolton-Hunter reagent) to the NK₁ receptors of humanlymphoblast cells.

2) The binding of [L¹²⁵ I]His-NKa to the NK₂ receptors of rat duodenumor bladder.

3) The binding of [¹²⁵ I]His[MePhe⁷ ]NK_(B) to the NK₃ receptors of ratcerebral cortex, of guinea pig cerebral cortex and of gerbil cerebralcortex, as well as to cloned human NK₃ receptors expressed by CHO cells(Buell et al., FEBS Letters, 1992, 299, 90-95).

The tests were performed according to X. Emonds-Alt et al., (Eur. J.Pharmacol., 1993, 250, 403-413).

The compounds according to the invention display an affinity for thetachykinin receptors mentioned above, with an inhibition constant Ki ofgenerally less than 10⁻⁸ M.

The compounds of the present invention are, in particular, activeprinciples of pharmaceutical compositions, the toxicity of which iscompatible with their use as medicinal products.

The compounds of the present invention are generally administered asdosage units. The said dosage units are preferably formulated inpharmaceutical compositions in which the active principle is mixed witha pharmaceutical excipient.

Thus, according to another of its aspects, the present invention relatesto pharmaceutical compositions containing as active principle a compoundof formula (I) or one of its pharmaceutically acceptable salts.

The compounds of formula (I) above and their pharmaceutically acceptablesalts may be used at daily doses of 0.01 to 100 mg per kilo body weightof the mammal to be treated, preferably at daily doses of 0.1 to 50mg/kg. In human beings, the dose can preferably vary from 0.5 to 4000 mgdaily, and more especially from 2.5 to 1000 mg according to the age ofthe subject to be treated or the type of treatment: prophylactic orcurative.

In the pharmaceutical compositions of the present invention for oral,sublingual, inhalation, subcutaneous, intramuscular, intravenous,transdermal, local or rectal administration, the active principles maybe administered in single-dose administration forms, mixed withtraditional pharmaceutical vehicles, to animals and to human beings.Suitable single-dose administration forms comprise forms for oraladministration such as tablets, gelatin capsules, powders, granules andoral solutions or suspensions, forms for sublingual and buccaladministration, aerosols, implants, forms for subcutaneous,intramuscular, intravenous, intranasal or intraocular administration andforms for rectal administration.

When a solid composition is prepared in the form of tablets, the mainactive principle is mixed with a pharmaceutical vehicle such as silica,gelatin, starch, lactose, magnesium stearate, talc, gum arabic or thelike. The tablets may be coated with sucrose, with various polymers orwith other suitable materials, or alternatively treated in such a waythat they have a sustained or delayed activity and that they release apredetermined amount of active principle continuously.

A preparation in gelatin capsules is obtained by mixing the activeprinciple with a diluent such as a glycol or a glycerol ester andincorporating the mixture obtained in hard or soft gelatin capsules.

A preparation in syrup or elixir form can contain the active principletogether with a sweetener, preferably of the non-caloric type,methylparaben and propylparaben as antiseptic, as well aflavour-imparting agent and a suitable colorant.

The water-dispersible powders or granules can contain the activeprinciple mixed with dispersing agents or wetting agents, or suspendingagents such as polyvinylpyrrolidone, as well as with sweeteners orflavour correctors.

For rectal administration, suppositories are employed, which areprepared with binding agents that melt at rectal temperature, forexample cocoa butter or polyethylene glycols.

For parenteral, intranasal or intraocular administration, aqueoussuspensions, isotonic saline solutions or sterile and injectablesolutions are used, which contain pharmacologically compatibledispersing agents and/or wetting agents, for example propylene glycol orbutylene glycol.

For administration by inhalation, an aerosol is used containing, forexample, sorbitan trioleate or oleic acid as well astrichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethaneor any other biologically compatible propellant gas; it is also possibleto use a system containing the active principle alone or combined withan excipient, in powder form.

The active principle may also be formulated in the form ofmicrocapsules, optionally with one or more vehicles or additives.

In each dosage unit, the active principle of formula (I) is present inthe amounts suited to the daily doses envisaged. In general, each dosageunit is appropriately adjusted according to the dosage and the type ofadministration planned, for example tablets, gelatin capsules and thelike, sachets, ampoules, syrups and the like, or drops, so that such adosage unit contains from 0.5 to 1000 mg of active principle, andpreferably from 2.5 to 250 mg, which doses are to be administered one tofour times daily.

The abovementioned compositions may also contain other active productssuch as, for example, bronchodilators, antitussives, antihistamines,anti-inflammatories, anti-emetics or chemotherapeutic agents.

According to another of its aspects, the present invention relates tothe use of the products of formula (I) for the preparation of medicinalproducts intended for treating physiological disorders associated withan excess of tachykinins, and all neurokinindependent pathologies of therespiratory, gastrointestinal, urinary, immune and cardiovascularsystems and the central nervous system, as well as pain and migraine.

For example and without limitation:

acute and chronic pains associated, for example, with migraine, withcancer and anginal pains, with chronic inflammatory processes such asosteoarthritis and rheumatoid arthritis,

inflammations such as neurogenic inflammations, chronic inflammatorydiseases, for example chronic obstructive respiratory diseases, asthma,allergies, rhinitis, coughs, bronchitis, hypersensitivity, for exampleto pollens and to mites, rheumatoid arthritis, fibrositis,osteoarthritis, psoriasis, ulcerative colitis, Crohn's disease,intestinal inflammation (irritable colon), prostatitis, neurologicalbladder, incontinence, cystitis, urethritis, nephritis, ophthalmicdiseases such as conjunctivitis, vitreoretinopathy, skin diseases suchas contact dermatitis, atopic dermatitis, urticaria, eczema, pruritus,burns, in particular sunburn,

diseases of the immune system associated with the suppression orstimulation of the functions of the immune cells, for example rheumatoidarthritis, psoriasis, Crohn's disease, diabetes, lupus, rejectionreactions after transplantation,

small cell cancer of the lung, demyelinating diseases such as multiplesclerosis or amyotropic lateral sclerosis,

diseases of the central nervous system of the neuropsychiatric orneurological type, such as anxiety, disorders of vigilance or of mood,depression, psychosis, schizophrenia, mania, dementia, epilepsy,Parkinson's disease, Alzheimer's disease, drug dependence, Down'ssyndrome and Huntington's chorea, as well as neurodegenerative diseasesand somatic disorders associated with stress,

diseases of the gastrointestinal system, such as nausea, vomiting of anyorigin, irritable colon, gastric and duodenal ulcers, oesophagealulcers, diarrhoea, hypersecretion,

diseases of the cardiovascular system such as hypertension, the vascularaspects of migraine, oedema, thrombosis, angina pectoris, vascularspasms, circulatory diseases due to a vasodilatation, Raynaud's disease,fibrosis, collagen diseases,

disorders of heart rate and rhythm, especially those caused by pain orstress.

The present invention also includes a method for treating the saidcomplaints at the doses indicated above.

In the preparations and in the examples, the following abbreviations areused:

Me, OMe: methyl, methoxy

Et, OEt: ethyl, ethoxy

EtOH: ethanol

MeOH: methanol

Ether: diethyl ether

Iso ether: diisopropyl ether

DMF: dimethylformamide

DMSO: dimethyl sulphoxide

DCM: dichloromethane

THF: tetrahydrofuran

AcOEt: ethyl acetate

K₂ CO₃ : potassium carbonate

Na₂ CO₃ : sodium carbonate

KHCO₃ : potassium hydrogen carbonate

NaHCO₃ : sodium hydrogen carbonate

NaCl: sodium chloride

Na₂ SO₄ : sodium sulphate

MgSO₄ : magnesium sulphate

NaOH: sodium hydroxide

AcOH: acetic acid

H₂ SO₄ : sulphuric acid

HCl: hydrochloric acid

ethereal hydrogen chloride: saturated solution of hydrochloric acid inether

BOP: benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate

KCN: potassium cyanide

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

NH₄ Cl: ammonium chloride

m.p.: melting point

RT: room temperature

silica H: silica gel 60H marketed by Merck (DARMSTADT)

NMR: nuclear magnetic resonance

δ: chemical shift

s: singlet

bs: broad singlet

ss: split singlet

d: doublet

t: triplet

qt: quartet

sept: septet

mt: multiplet

uc: unresolved complex

PREPARATION 1.1

4-(2-Hydroxyethoxy)-4-phenylpiperidine hydrochloride.

A) 1-Benzyl-4-hydroxy-4-phenylpiperidine.

This compound is prepared by the action of phenyllithium on1-benzyl-4-piperidone according to the process described in EP-A-474561.

B) 4-(Benzoyloxy)1-benzyl-4-phenylpiperidine.

A solution of 2.67 g of the compound prepared in the preceding step, 2.5ml of triethylamine and 30 ml of DCM is cooled to 0-5° C., 1.22 ml ofbenzoyl chloride are added and the mixture is left stirring for 1 hourwhile allowing the temperature to rise to RT. The reaction mixture isconcentrated under vacuum, the residue is extracted with AcOEt, theorganic phase is washed with water and with iN NaOH solution and driedover MgSO₄ and the solvent is evaporated off under vacuum. 2.4 g of theexpected product are obtained after crystallization in pentane.

C) 1-Benzyl-4-(2-hydroxyethoxy)-4-phenylpiperidine hydrochloride.

A mixture of 2.3 g of the compound obtained in the preceding step, 7 mlof H₂ SO₄ and 60 ml of ethylene glycol is heated to 60° C. for 5 hours.The reaction mixture is poured onto ice and alkalinized by addingconcentrated NH₄ OH solution, the product is extracted with DCM, theorganic phase is washed with water and dried over MgSO₄ and the solventis evaporated off under vacuum. The residue is chromatographed onsilica, eluting with DCM and then with a DCM/MeOH (96:4; v/v) mixture.The product obtained is dissolved in DCM, the mixture is acidified to pH1 by adding ethereal hydrogen chloride and the precipitate formed isdrained. 1 g of the expected product is obtained.

D) 4-(2-Hydroxyethoxy)-4-phenylpiperidine hydrochloride.

A mixture of 3.3 g of the compound obtained in the preceding step and0.4 g of palladium on charcoal (10% Pd) in 100 ml of EtOH ishydrogenated at RT and at atmospheric pressure. The catalyst is filteredoff on Celite® and the filtrate is concentrated under vacuum. 2.2 g ofthe expected product are obtained, m.p.=168-172° C.

PREPARATION 1.2.

4-(2-Methoxyethoxy)-4-phenylpiperidine hydrochloride.

A) 1-Benzyl-4-(2-methoxyethoxy)-4-phenylpiperidine hydrochloride.

A solution of 4.7 g of the compound obtained in step B of PREPARATION1.1 in 50 ml of 2-methoxyethanol is cooled to 5° C., 10 ml of H₂ SO₄ areadded dropwise, and the reaction mixture is left stirring while allowingthe temperature to rise to RT and is then heated to 30-40° C. for 4hours. The reaction mixture is poured onto ice and alkalinized to pH 10by adding concentrated NH₄ OH solution, the product is extracted withDCM, the organic phase is washed with water and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica, eluting with DCM and then with a DCM/MeOH (99:1; v/v)mixture. The product obtained is dissolved in DCM, the mixture isacidified to pH 1 by adding ethereal hydrogen chloride and theprecipitate formed is drained. 1.5 g of the expected product areobtained.

B) 4-(2-Methoxyethoxy)-4-phenylpiperidine hydrochloride

A mixture of 1.5 g of the compound obtained in the preceding step and0.18 g of palladium on charcoal (10% Pd) in 50 ml of EtOH ishydrogenated at RT and at atmospheric pressure. The catalyst is filteredoff on Celite® and the filtrate is concentrated under vacuum. 0.8 g ofthe expected product is obtained.

PREPARATION 1.3.

4-(Formylamino)-4-phenylpiperidine hydrochloride.

A) 4--Acetamido-1-benzyl-4-phenylpiperidine.

This compound is prepared by the action of acetonitrile on the compoundobtained in step A of PREPARATION 1.1 according to the process describedin EP-A-474561.

B) 4-Amino-1-benzyl-4-phenylpiperidine dihydrochloride.

A mixture of 50 g of the compound obtained in the preceding step and 90ml of concentrated HCl solution in 210 ml of water is heated to refluxfor 48 hours. The reaction mixture is concentrated under vacuum, theresidue is taken up in an EtOH/toluene mixture and the solvents areevaporated off under vacuum. The residue is dissolved in 100 ml of hotMeOH, 500 ml of acetone are added and the mixture is left stirring whilecooling in an ice bath. The crystals formed are drained, washed withacetone and then with ether and dried. 48.9 g of the expected productare obtained.

C) 1-Benzyl-4-(formylamino)-4-phenylpiperidine hydrochloride.

4.5 ml of acetic anhydride are added dropwise to a solution of 2 g ofthe compound obtained in the preceding step and 0.9 g of sodium formatein 14 ml of formic acid, and the mixture is left stirring for 48 hoursat RT. It is concentrated under vacuum, the residue is taken up withwater and alkalinized by adding concentrated NaOH, the product isextracted with DCM, the organic phase is dried over MgSO₄ and thesolvent is evaporated off under vacuum. The product obtained is taken upin DCM, and the mixture is acidified to pH 1 by adding ethereal hydrogenchloride and evaporated under vacuum. 1.7 g of the expected product areobtained after crystallization in acetone, m.p.=225° C. (dec).

D) 4-(Formylamino)-4-phenylpiperidine hydrochloride.

A mixture of 1.7 g of the compound obtained in the preceding step, 0.2 gof palladium on charcoal (10% Pd) and 50 ml of 95% EtOH is hydrogenatedat RT and at atmospheric pressure. The catalyst is filtered off and thefiltrate is evaporated under vacuum. 1.1 g of the expected product areobtained after crystallization in acetone, m.p.=217° C.

PREPARATION 1.4.

4-(Acetyl-N-methylamino)-4-phenylpiperidine p-toluenesulphonate.

A) 1-Benzyl-4-(formylamino)-4-phenylpiperidine.

110 ml of acetic anhydride are added dropwise to a solution of 48.9 g ofthe compound obtained in step B of PREPARATION 1.3 and 25 g of sodiumformate in 340 ml of formic acid, and the reaction mixture is leftstirring overnight at RT. It is concentrated under vacuum, the residueis taken up in water and alkalinized by adding concentrated NaOHsolution, the product is extracted with DCM, the organic phase is driedover MgSO₄ and the solvent is evaporated off under vacuum. 38.8 g of theexpected product are obtained after crystallization in an isoether/pentane mixture, m.p.=140° C.

B) 1-Benzyl-4-(methylamino)-4-phenylpiperidine.

A solution of 38.8 g of the compound obtained in the preceding step in400 ml of THF is added slowly to a suspension of 12.5 g of lithiumaluminium hydride in 100 ml of THF, and the mixture is heated to refluxfor 3 hours. After cooling, a concentrated solution of 5 ml of NaOH in45 ml of water is added to the reaction mixture, the inorganic salts arefiltered off and the filtrate is concentrated under vacuum. 38 g of theexpected product are obtained.

C) 4-(Acetyl-N-methylamino)-1-benzyl-4-phenylpiperidine.

A solution of 30 g of the compound obtained in the preceding step and16.5 ml of triethylamine in 300 ml of DCM is cooled to 0-5° C., 8 ml ofacetyl chloride are added dropwise and the reaction mixture is leftstirring for 30 minutes at RT. It is washed twice with water and with 2NNaOH solution, the organic phase is dried over MgSO₄ and the solvent isevaporated off under vacuum. 31.6 g of the expected product are obtainedafter crystallization in an iso ether/pentane mixture, m.p.=104° C.

D) 4-(Acetyl-N-methylamino)-4-phenylpiperidine p-toluenesulphonate.

A mixture of 5 g of the compound obtained in the preceding step, 2.9 gof p-toluenesulphonic acid monohydrate, 0.5 g of palladium on charcoal(100% Pd) and 80 ml of EtOH is hydrogenated for 3 hours at 25° C. and atatmospheric pressure. The catalyst is filtered off and the filtrate isconcentrated under vacuum. 5.7 g of the expected product are obtainedafter crystallization in acetone, m.p.=165° C.

PREPARATION 1.5.

4-(Methoxycarbonylamino)-4-phenylpiperidine p-toluenesulphonatehemihydrate.

A) 1-tert-Butoxycarbonyl-4-carboxy-4-phenylpiperidine.

32.9 g of K₂ CO₃ are added to a mixture of 30 g of4-carboxy-4-phenylpiperidine p-toluenesulphonate in 300 ml of dioxaneand 30 ml of water, the mixture is then heated to 60° C. and 18.2 g ofdi-tert-butyl dicarbonate are added dropwise. The mixture is thereafterheated for 2 hours to 60° C. and then for 30 minutes to reflux. Aftercooling to RT, the reaction mixture is concentrated under vacuum, theresidue is extracted with DCM, the organic phase is washed with a pH 2buffer solution, with 2N HCl solution to pH 4, with a pH 2 buffersolution, with water and with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum. 23.7 g of theexpected product are obtained.

B) 1-tert-butoxycarbonyl-4-isocyanato-4-phenylpiperidine.

A solution of 25 g of the compound obtained in the preceding step and10.35 g of triethylamine in 100 ml of acetone is cooled to 0-5° C., asolution of 8.7 g of methyl chloroformate in 30 ml of acetone is addeddropwise at a temperature below 5° C., and the mixture is left stirringfor 30 minutes. A solution of 10.66 g of sodium azide in 30 ml of wateris then added at a temperature below 5° C., and the reaction mixture isleft stirring for 30 minutes. It is poured into 500 ml of ice-cold waterand extracted four times with 130 ml of toluene, and the combinedorganic phases are washed twice with a pH 2 buffer solution and withsaturated NaCl solution, dried over MgSO₄ and filtered. The filtrate isheated to 90° C. for 1 hour and then concentrated under vacuum. 18.9 gof the expected product are obtained in the form of an oil.

C) 4-(Methoxycarbonylamino)-4-phenylpiperidine p-toluenesulphonatehemihydrate.

A solution of 6.05 g of the compound obtained in the preceding step in100 ml of MeOH is heated to reflux for 5 hours. 1 drop of triethylamineis added and the mixture is left stirring overnight at RT. ConcentratedHCl solution is then added to pH 1 and the reaction mixture isconcentrated under vacuum. The residue is taken up with 10% NaOHsolution, the product is extracted with DCM, the organic phase is washedwith 10% NaOH solution and with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum. The productobtained is dissolved in acetone, a solution of 3.57 g ofp-toluenesulphonic acid monohydrate in 10 ml of acetone is addeddropwise and the mixture is concentrated under vacuum. The productobtained is taken up in ether and the solvent is evaporated off undervacuum. 7.17 g of the expected product are obtained, m.p.=159° C.

PREPARATION 1.6.

4-(Ethoxycarbonylamino)-4-phenylpiperidine trifluoroacetate.

A) 1-(tert-butoxycarbonyl-4-(ethoxycarbonylamino)-4-phenylpiperidine.

A solution of 6.28 g of the compound obtained in step B of PREPARATION1.5 in 100 ml of EtOH is heated to reflux for 5 hours 30 minutes. A dropa triethylamine is added, and the reaction mixture is then left stirringovernight at RT and concentrated under vacuum. 7.25 g of the expectedproduct are obtained, which is used without further treatment.

B) 4-(Ethoxycarbonylamino)-4-phenylpiperidine trifluoroacetate.

A solution of 7.25 g of the compound obtained in the preceding step in20 ml of TFA is left stirring for 5 minutes at RT and concentrated undervacuum. The residue is taken up in acetone and the solvent is evaporatedoff under vacuum. The oil obtained is dissolved in a minimum of acetone,ether is added until precipitation takes place and the mixture is leftstirring overnight at RT. 6.02 g of the expected product are obtainedafter draining and drying, m.p.=173° C.

PREPARATION 1.7.

4-(Methanesulphonamido)-4-phenylpiperidine p-toluenesulphonate.

A) 1-Benzyl-4-(methanesulphonamido)-4-phenylpiperidine.

A solution of 6 g of the compound obtained in step B of PREPARATION 1.3and 5.71 g of triethylamine in 100 ml of DCM is cooled to 0-5° C., 2.22g of methanesulphonyl chloride are added dropwise and the mixture isleft stirring for 30 minutes at RT. A further 0.2 ml of methanesulphonylchloride is added and stirring is continued for 2 hours. The reactionmixture is concentrated under vacuum, the residue is extracted with DCM,the organic phase is washed with 10% NaOH solution, with water and withsaturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. 6.6 g of the expected product are obtained.

B) 4-(Methanesulphonamido)-4-phenylpiperidine p-toluenesulphonate.

A mixture of 6.6 g of the compound obtained in the preceding step, 3.64g of p-toluenesulphonic acid monohydrate and 0.66 g of palladium oncharcoal (10% Pd) in 100 ml of EtOH is hydrogenated for 6 hours in aParr apparatus at 45° C. and at a pressure of 17 bars. The catalyst isfiltered off and the filtrate is concentrated under vacuum. 2.08 g ofthe expected product are obtained after crystallization in anacetone/ether (50:50; v/v) mixture.

PREPARATION 1.8.

4-(3-Ethylureido)-4-phenylpiperidine p-toluenesulphonate.

A) 1-tert-Butoxycarbonyl-4-(3-ethylureido)-4-phenylpiperidine. 1.55 g ofa 70% solution of ethylamine in water and diluted in 10 ml of acetoneare added dropwise at RT to a solution of 6.05 g of the compoundobtained in step B of PREPARATION 1.5 in 100 ml of acetone. The reactionmixture is concentrated under vacuum, the residue is extracted withAcOEt, the organic phase is washed with a pH 2 buffer solution and withsaturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. 5.8 g of the expected product are obtainedafter crystallization in ether.

B) 4-(3-Ethylureido)-4-phenylpiperidine p-toluenesulphonate.

10 ml of concentrated HCl solution are added to a solution of 5.7 g ofthe compound obtained in the preceding step in 60 ml of MeOH, and thereaction mixture is left stirring overnight at RT. It is concentratedunder vacuum, the residue is taken up with 10% NaOH solution, theproduct is extracted three times with DCM, the combined organic phasesare washed three times with 10% NaOH solution and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum. The product obtained (1.7 g) is dissolved in 20 ml of anacetone/MeOH (90:10; v/v) mixture, a solution of 1.31 g ofp-toluenesulphonic acid monohydrate in 5 ml of acetone is added dropwiseand the crystallized product formed is drained. 1.9 g of the expectedproduct are obtained, m.p.=225° C.

PREPARATION 1.9

4-(3-Cyclopentylureido)-4-phenylpiperidine p-toluenesulphonate.

A) 1-tert-Butoxycarbonyl-4-(3-cyclopentylureido)-4-phenylpiperidine.

A solution of 2.04 g of cyclopentylamine in 10 ml of acetone is addeddropwise at RT to a solution of 6.05 g of the compound obtained in stepB of PREPARATION 1.5 in 100 ml of acetone. The reaction mixture isconcentrated under vacuum, the residue is taken up in ether and thecrystallized product formed is drained. 7.4 g of the expected productare obtained.

B) 4-(3-Cyclopentylureido)-4-phenylpiperidine p-toluenesulphonate.

15 ml of concentrated HCl solution are added to a solution of 7.33 g ofthe compound obtained in the preceding step in 70 ml of MeOH, and thereaction mixture is left stirring for 7 hours at RT. It is concentratedunder vacuum, the residue is taken up with 10 ml of water, the mixtureis alkalinized to pH 12 by adding concentrated NaOH solution, 300 ml ofDCM are added and the mixture is left stirring until the gummy producthas been solubilized. After settling has taken place, the aqueous phaseis separated and extracted three times with 150 ml of DCM, the combinedorganic phases are washed with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum. The productobtained (3.8 g) is dissolved in 40 ml of an acetone/MeOH (90:10; v/v)mixture, a solution of 2.5 g of p-toluenesulphonic acid monohydrate in10 ml of acetone is added dropwise and the crystallized product formedis drained. 4 g of the expected product are obtained, m.p.=252° C.

PREPARATION 1.10.

4-(3,3-Dimethylureido)-4-phenylpiperidine p-toluenesulphonatehemihydrate.

A) 1-Benzyl-4-(3,3-dimethylureido)-4-phenylpiperidine.

A solution of 1.9 g N,N-dimethylcarbamoyl chloride in 10 ml of1,2-dichloroethane is added dropwise at RT to a solution of 6 g of thecompound obtained in step B of PREPARATION 1.3 and 7.14 g oftriethylamine in 50 ml of 1,2-dichloroethane, and the mixture is heatedto reflux for 8 hours. A further few drops of N,N-dimethylcarbamoylchloride are added and refluxing is continued for 3 hours. The reactionmixture is concentrated under vacuum, the residue is extracted with DCM,the organic phase is washed with water, with 10% NaOH solution, withwater and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica, eluting with a DCM/MeOH mixture gradient from (99:1; v/v) to(96:4; v/v). 1.8 g of the expected product are obtained.

B) 4-(3,3-Dimethylureido)-4-phenylpiperidine p-toluenesulphonatehemihydrate.

A mixture of 1.8 g of the compound obtained in the preceding step, 1.11g of p-toluenesulphonic acid monohydrate and 0.2 g of palladium oncharcoal (10% Pd) in 150 ml of 95% EtOH is hydrogenated at 400 and atatmospheric pressure. The catalyst is filtered on Celite® and thefiltrate is evaporated under vacuum. The residue is taken up in acetoneand the solvent is evaporated off under vacuum. The product obtained isdissolved in 25 ml of acetone, this solution is added slowly to 200 mlof ether and the crystallized product formed is drained. 1.86 g of theexpected product are obtained, m.p.=120-122° C.

PREPARATION 1.11.

4-Benzyl-4-(3,3-dimethylureido)piperidine p-toluenesulphonate.

A) 1,4-Dibenzyl-4-cyanopiperidine.

A solution of 15 g of 4-cyanopiperidine in 250 ml of THF is cooled to-50° C., 190 ml of a 1.5M solution of lithium diisopropylamide incyclohexane is added dropwise and the mixture is left stirring for 30minutes at -50° C. 34 ml of benzylbromide are then added slowly and themixture is left stirring for 3 hours while allowing the temperature torise to RT.

The reaction mixture is poured into an ice/concentrated HCl mixture,ether is added and the precipitate formed is drained and washed withwater. The precipitate is taken up in water, the mixture is alkalinizedto pH 12 by adding concentrated NaOH solution and extracted with ether,the organic phase is dried over MgSO₄ and the solvent is evaporated offunder vacuum. 31.7 g of the expected product are obtained aftercrystallization in pentane, m.p.=92° C.

B) 1,4-Dibenzyl-4-carboxypiperidine.

A mixture of 6 g of the compound obtained in the preceding step, 25 mlof H₂ SO₄, 25 ml of AcOH and 25 ml of water is heated to 140° C. for 5hours. The reaction mixture is poured onto ice, concentrated NaOHsolution is added until the pH=6.5 and the mixture is left stirringuntil the product has crystallized. The crystals formed are drained,washed with water and dried. 5.2 g of the expected product are obtainedafter recrystallization in MeOH, m.p.=262° C.

C) 1.4-Dibenzyl-4-(3,3-dimethylureido)piperidine.

0.4 g of phosphorus pentachloride is added at RT to a solution of 0.5 gof the compound obtained in the preceding step in 10 ml of chloroform,and the reaction mixture is heated to 60° C. for 1 hour. It isconcentrated under vacuum, the residue is dissolved in 5 ml of DCM, thissolution is added to a solution of 0.35 g of sodium azide in 5 ml ofacetone and the reaction mixture is left stirring for 2 hours at RT. Itis concentrated at RT under vacuum, the residue is extracted with ether,the organic phase is washed with saturated Na₂ CO₃ solution and withwater and dried over MgSO₄ and the solvent is evaporated off undervacuum. The product obtained is taken up in 10 ml of toluene and themixture is heated to reflux for 2 hours. After cooling to RT, 2 ml of a33% solution of dimethylamine in ethanol are added, and the reactionmixture is left stirring for 15 minutes and concentrated under vacuum.0.43 g of the expected product is obtained after crystallization in aniso ether/pentane mixture, m.p.=131° C.

D) 4-Benzyl-4-(3,3-dimethylureido)piperidine p-toluenesulphonate.

A mixture of 0.43 g of the compound obtained in the preceding step,0.233 g of p-toluenesulphonic acid monohydrate and 0.05 g of palladiumon charcoal (10% Pd) in 10 ml of EtOH is hydrogenated at RT and atatmospheric pressure for 24 hours. The catalyst is filtered off and thefiltrate is concentrated under vacuum. 0.54 g of the expected product isobtained after crystallization in acetone, m.p.=140° C.

PREPARATION 1.12.

4-(3,3-Diethylureido)-4-phenylpiperidine p-toluenesulphonatehemihydrate.

A) 1-tert-Butoxycarbonyl-4-(3,3-diethylureido)-4-phenylpiperidine.

A solution of 1.16 g of diethylamine in 10 ml of acetone is addeddropwise at RT to a solution of 6.05 g of the compound obtained in stepB of PREPARATION 1.5 in 100 ml of acetone. The reaction mixture isconcentrated under vacuum, the residue is extracted with ether, theorganic phase is washed with a pH 2 buffer solution and with saturatedNaCl solution and dried over MgSO₄ and the solvent is evaporated offunder vacuum. 7.2 g of the expected product are obtained.

B) 4-(3,3-Diethylureido)-4-phenylpiperidine p-toluenesulphonatehemihydrate.

15 ml of concentrated HCl solution are added to a solution of 7.1 g ofthe compound obtained in the preceding step in 70 ml of MeOH, and thereaction mixture is left stirring overnight at RT. It is concentratedunder vacuum, the residue is taken up with 10% NaOH solution, theproduct is extracted three times with DCM, the combined organic phasesare washed three times with 10% NaOH solution and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum. The product obtained (5.1 g) is dissolved in 50 ml of acetone, asolution of 3.52 g of p-toluenesulphonic acid monohydrate in 15 ml ofacetone is added dropwise and the mixture is concentrated under vacuum.The residue is taken up in AcOEt, MeOH is added until the gummy productformed has dissolved and the mixture is concentrated under vacuum. Theresidue is taken up in ether, and the mixture is left stirring overnightat RT and concentrated under vacuum. 7.7 g of the expected product areobtained after drying, m.p.=95° C.

PREPARATION 1.13.

4-Phenyl-4-(1-pyrrolidinylcarbonylamino)piperidine p-toluenesulphonate.

A)1-tert-butoxycarbonyl-4-phenyl-4-(1-pyrrolidinylcarbonylamino)piperidine.

A solution of 4.5 g of the compound obtained in step B of PREPARATION1.5 in 60 ml of 1,2-dichloroethane is heated to reflux, 1.1 g ofpyrrolidine are added and the mixture is left stirring overnight whileallowing the temperature to fall to RT. The reaction mixture isconcentrated under vacuum, the residue is extracted with ether, theorganic phase is washed with a pH 2 buffer solution, with water, with 5%NaHCO₃ solution, with water and with saturated NaCl solution and driedover MgSO₄ and solvent is evaporated off under vacuum. 4.4 g of theexpected product are obtained in the form of an oil.

B) 4-Phenyl-4-(1-pyrrolidinylcarbonylamino)piperidinep-toluenesulphonate.

8 ml of concentrated HCl solution are added to a solution of 4.4 g ofthe compound obtained in the preceding step in 50 ml of MeOH, and thereaction mixture is left stirring overnight at RT. It is concentratedunder vacuum, the residue is taken up in water, the mixture isalkalinized by adding 10% NaOH solution, the product is extracted withDCM, the organic phase is washed with water and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum. The product obtained (2.78 g) is dissolved in 50 ml of acetone,1.42 g of p-toluenesulphonic acid monohydrate are added and the mixtureis concentrated under vacuum. 3.85 g of the expected product areobtained after crystallization in AcOEt.

PREPARATION 1.14.

4-(N-Methylcarbamoyl)-4-phenylpiperidine.

A) 1-tert-Butoxycarbonyl-4-(N-methylcarbamoyl)-4-phenylpiperidine.

5.29 g of triethylamine and then 1.32 g of methylamine hydrochloride areadded to a solution of 4 g of the compound obtained in step A ofPREPARATION 1.5 in 20 ml of a DCM/DMF (50:50; v/v) mixture, theresulting mixture is cooled to 0-5° C., 6.37 g of BOP are added and thereaction mixture is left stirring for 24 hours at RT. It is concentratedunder vacuum, the residue is extracted with ether, the organic phase iswashed with water, with a pH 2 buffer solution, with water, with 10%NaOH solution, with water and with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum. 3.72 g of theexpected product are obtained.

B) 4-(N-methylcarbamoyl)-4-phenylpiperidine.

8 ml of concentrated HCl solution are added to a solution of 3.7 g ofthe compound obtained in the preceding step in 60 ml of MeOH, and themixture is left stirring for 1 hour at RT. It is concentrated undervacuum, the residue is taken up with 10t NaOH solution, the product isextracted with DCM, the organic phase is washed with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum. 1.95 g of the expected product are obtained.

PREPARATION 1.15

4-(Ethylaminocarbonyloxymethyl)-4-phenylpiperidine hydrochloride.

A) 4-Methoxycarbonyl-4-phenylpiperidine p-toluenesulphonate.

1 g of p-toluenesulphonic acid monohydrate is added to a solution of 10g of 4-carboxy-4-phenylpiperidine p-toluenesulphonate in 300 ml of MeOH,and the reaction mixture is heated to reflux for 3 days. It isconcentrated under vacuum, the residue is taken up in acetone and etheris added until precipitation takes place. After draining of theprecipitate formed, 9.34 g of the expected product are obtained.

B) 4-Hydroxymethyl-4-phenylpiperidine.

A suspension of 1.16 g of lithium aluminium hydride in 50 ml of THF iscooled to -20° C., 4 g of the compound obtained in the preceding stepare added and the mixture is left stirring overnight while allowing thetemperature to rise to RT. The mixture is hydrolysed by adding 1.2 ml ofwater, then 2.5 ml of 10% NaOH solution and 2.5 ml of water. It isdiluted with ether, the inorganic salts are filtered off and thefiltrate is evaporated under vacuum. 1.8 g of the expected product areobtained.

C) 1-tert-Butoxycarbonyl-4-(hydroxymethyl)-4-phenylpiperidine.

26.05 g of di-tert-butyl dicarbonate are added to a solution of 22.8 gof the compound obtained in the preceding step in 250 ml of1,2-dimethoxyethane, and the reaction mixture is heated to reflux for 2hours. It is concentrated under vacuum, the residue is taken up in DCM,the organic phase is washed with a pH 2 buffer solution and withsaturated NaCl solution and dried over MgSO4 and the solvent isevaporated off under vacuum. 17.86 g of the expected product areobtained after crystallization in ether, m.p.=134° C.

D)1-tert-Butoxycarbonyl-4-(ethylaminocarbonyloxymethyl)-4-phenylpiperidine.

A mixture of 2.91 g of the compound obtained in the preceding step, 2.4g of ethyl isocyanate and 2 drops of triethylamine in 30 ml of tolueneis left stirring overnight at RT. The reaction mixture is then heated to100° C. for 24 hours and concentrated under vacuum. The residue is takenup in ether, the organic phase is washed with a pH 2 buffer solution andwith saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. 3.85 g of the expected product are obtainedin the form of an oil.

E) 4-(Ethylaminocarbonyloxymethyl)-4-phenylpiperidine hydrochloride.

10 ml of concentrated HCl are added to a solution of 3.85 g of thecompound obtained in the preceding step in 50 ml of MeOH, and themixture is heated to 60° C. for 2 hours. It is concentrated undervacuum, the residue is taken up in acetone and the solvent is evaporatedoff under vacuum. 2.6 g of the expected product are obtained aftercrystallization in an AcOEt/ether mixture, m.p.=240-242° C.

PREPARATION 1.16.

4-(Acryloyl-N-methylamino)-4-phenylpiperidine hydrochloride.

A) 4-(Acryloyl-N-methylamino)-1-benzyl-4-phenylpiperidine.

A solution of 1.5 g of the compound obtained in step B of PREPARATION1.4 and 1.5 ml of triethylamine in 40 ml of DCM is cooled to 0-5° C.,0.5 ml of acryloyl chloride is added dropwise and the mixture is leftstirring while allowing the temperature to rise to RT. The reactionmixture is poured into water, the organic phase is separated aftersettling has taken place and washed with water and with 2N NaOH solutionand dried over MgSO₄ and the solvent is evaporated off under vacuum. 1.3g of the expected product are obtained after crystallization in anether/pentane mixture.

B) 4-(Acryloyl-N-methylamino)-4-phenylpiperidine hydrochloride.

A solution of 1.3 g of the compound obtained in the preceding step in 30ml of 1,2-dichloroethane is cooled to 0° C., 0.5 ml of 1-chloroethylchloroformate is added dropwise and the reaction mixture is then heatedto reflux for 2 hours. It is concentrated under vacuum, the residue istaken up in 15 ml of MeOH, and the mixture is heated to reflux for 30minutes and concentrated under vacuum. 0.65 g of the expected product isobtained after crystallization in AcOET.

PREPARATION 1.17.

4-Phenyl-4-(propionyl-N-methylamino)piperidine p-toluenesulphonate.

A) 4-(Acryloyl-N-methylamino)-1-benzyl-4-phenylpiperidinep-toluenesulphonate.

0.59 g of p-toluenesulphonic acid monohydrate is added to a solution of1.15 g of the compound obtained in step A of PREPARATION 1.16 in 10 mlof DCM, and the mixture is left for crystallization to take place. 1.65g of the expected product are obtained.

B) 4-Phenyl-4-(propionyl-N-methylamino)piperidine p-toluenesulphonate.

A mixture of 1.64 g of the compound obtained in the preceding step and0.2 g of palladium on charcoal (100% Pd) in 100 ml of EtOH ishydrogenated at RT and at atmospheric pressure. The catalyst is filteredoff on Celite® and the solvent is evaporated off under vacuum. 1.3 g ofthe expected product are obtained.

PREPARATION 1.18.

4-(Cyclopropylcarbonylamino)-4-phenylpiperidine hydrochloride.

A) 1-Benzyl-4-(cyclopropylcarbonylamino)-4-phenylpiperidine.

A solution of 1 g of the compound obtained in step B of PREPARATION 1.3and 1.7 ml of triethylamine in 30 ml of DCM is cooled to -20° C., 0.22ml of cyclopropanecarbonyl chloride is added dropwise and the mixture isleft stirring while allowing the temperature to rise to RT. The reactionmixture is extracted with DCM, the organic phase is washed twice withwater and with 0.5N NaOH solution and dried over MgSO₄ and the solventis evaporated off under vacuum. The residue is taken up in AcOEt, andthe crystals formed are drained and washed with AcOEt and then withether. 0.77 g of the expected product is obtained.

B) 4-(Cyclopropylcarbonylamino)-4-phenylpiperidine hydrochloride.

A mixture of 0.77 g of the compound obtained in the preceding step, 0.14g of palladium on charcoal (10% Pd) and 40 ml of EtOH is hydrogenated at35° C. and at atmospheric pressure. The catalyst is filtered off and thefiltrate is evaporated off under vacuum. The residue is taken up in DCM,and the mixture is acidified to pH 1 by adding ethereal hydrogenchloride and evaporated under vacuum. 0.6 g of the expected product isobtained.

Proton NMR spectrum at 200 MHz in DMSO-d₆.

δ: 0.5 to 0.9 ppm: uc: 4H

1.9 ppm: mt: 1H

2.05 to 2.7 ppm: uc: 4H

3.0 to 3.5 ppm uc: 4H

7.2 to 7.6 ppm uc: 5H

8.6 ppm: s: 1H

9.0 ppm: s: 2H

PREPARATION 1.19.

4-(Cyclobutylcarbonylamino)-4-phenylpiperidine p-toluenesulphonate.

A) 1-Benzyl-4-(cyclobutylcarbonylamino)-4-phenylpiperidinep-toluenesulphonate.

A solution of 1.5 g of the compound obtained in step B of PREPARATION1.3 and 2.1 ml of triethylamine in 30 ml of DCM is cooled to 0° C., 0.45ml of cyclobutanecarbonyl chloride is added dropwise and the mixture isleft stirring while allowing the temperature to rise to RT. The mixtureis extracted with DCM, the organic phase is washed twice with water andwith 0.5N NaOH solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. The product obtained is dissolved in DCM,0.6 g of p-toluenesulphonic acid monohydrate is added and the mixture isleft for crystallization to take place. 1.7 g of the expected productare obtained.

B) 4-(Cyclobutylcarbonylamino)-4-phenylpiperidine p-toluenesulphonate.

A mixture of 1.69 g of the compound obtained in the preceding step, 0.2g of palladium on charcoal (10% Pd) and 100 ml of EtOH is hydrogenatedat 35° C. and at atmospheric pressure. The catalyst is filtered off onCelite® and the filtrate is evaporated under vacuum. 1.35 g of theexpected product are obtained.

PREPARATION 1.20.

4-(Cyclohexylcarbonyl-N-methylamino)-4-phenylpiperidinep-toluenesulphonate.

A) 1-Benzyl-4-(cyclohexylcarbonyl-N-methylamino)-4-phenylpiperidinep-toluenesulphonate.

0.78 ml of cyclohexanecarbonyl chloride is added dropwise at RT to asolution of 1.5 g of the compound obtained in step B of PREPARATION 1.4and 1.5 ml of triethylamine in 15 ml of DCM, and the reaction mixture isleft stirring for 2 hours. It is washed twice with water and with 2NNaOH solution, the organic phase is dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is dissolved in DCM, 0.97 g ofp-toluenesulphonic acid monohydrate is added and the mixture isconcentrated under vacuum. 3.3 g of the expected product are obtainedafter crystallization in an AcOEt/ether mixture.

B) 4-(Cyclohexylcarbonyl-N-methylamino)-4-phenylpiperidinep-toluenesulphonate.

A mixture of 3.3 g of the compound obtained in the preceding step and0.35 g of palladium on charcoal (10% Pd) in 100 ml of EtOH ishydrogenated at RT and at atmospheric pressure. The catalyst is filteredoff and the filtrate is evaporated under vacuum. The residue is taken upin acetone and the solvent is evaporated off under vacuum. 2.2 g of theexpected product are obtained after crystallization in an AcOEt/ethermixture, m.p.=160° C.

PREPARATION 1.21.

4-Phenyl-4-(1-pyrrolidinylcarbonyl)piperidine hemihydrate.

A) 1-tert-Butoxycarbonyl-4-carboxy-4-phenylpiperidine.

30 ml of water and 32.9 g of K₂ CO₃ are added to a mixture of 30 g of4-carboxy-4-phenylpiperidine p-toluenesulphonate in 300 ml of dioxane,the mixture is then heated to 60° C. and 18.2 g of di-tert-butyldicarbonate are added dropwise. The mixture is thereafter heated for 2hours to 60° C. and then for 30 minutes to reflux. After cooling to RT,the reaction mixture is concentrated under vacuum, the residue isextracted with DCM, the organic phase is washed with a pH 2 buffersolution, acidified to pH 4 by adding 2N HCl, washed with a pH 2 buffersolution, with water and with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum. 23.7 g of theexpected product are obtained.

B) 1-tert-Butoxycarbonyl-4-(1-pyrrolidinylcarbonyl)-4-phenylpiperidine.

9.29 g of triethylamine and then 3.27 g of pyrrolidine are added to asolution of 14 g of the compound obtained in the preceding step in 200ml of DCM. The mixture is cooled in an ice bath, 22.4 g of BOP are addedand the mixture is left stirring while allowing the temperature to riseto RT. The reaction mixture is concentrated under vacuum, the residue isextracted with DCM, the organic phase is washed with water, three timeswith 10% NaOH solution, with water, three times with a pH 2 buffersolution, with water and with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum. 16.4 g of theexpected product are obtained.

C) 4-Phenyl-4-(1-pyrrolidinylcarbonyl)piperidine hemihydrate.

Concentrated HCl solution is added to a solution of 16.4 g of thecompound obtained in the preceding step in 200 ml of MeOH until thepH=1, and the reaction mixture is left stirring for 5 hours at RT. It isconcentrated under vacuum, the residue is taken up in acetone and thesolvent is evaporated off under vacuum. A white solid is obtained, whichis recrystallized in 2-propanol. The product obtained is taken up with10% NaOH solution, the mixture is extracted with DCM, the organic phaseis washed with 10 NaOH solution and with saturated NaCl solution anddried over MgSO₄ and the solvent is evaporated off under vacuum. 7 g ofthe expected product are obtained after crystallization in ether,m.p.=126° C.

PREPARATION 1.22.

4-(Carboxymethyl)-4-phenylpiperidine hydrobromide.

The preparation of this compound is described in Chem. Per., 1975, 108,3475-3482.

PREPARATION 1.23.

4-(N,N-Dimethylcarbamoyl)-4-phenylpiperidine.

A) 1-tert-Butoxycarbonyl-4-(N,N-dimethylcarbamoyl)-4-phenylpiperidine.

8.1 g of triethylamine and then 4.9 g of dimethylamine hydrochloride areadded to a solution of 6.11 g of the compound obtained in step A ofPREPARATION 1.21 in 20 ml of DCM and 20 ml of DMF. The mixture is cooledin an ice bath, 9.73 g of BOP are added and the mixture is left stirringfor 3 hours while allowing the temperature to rise to RT. The mixture isconcentrated under vacuum, the residue is extracted with ether, theorganic phase is washed with water, with a pH 2 buffer solution, with10% NaOH solution, with water and with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum. 6.45 g of theexpected product are obtained.

B) 4-(N,N-Dimethylcarbamoyl)-4-phenylpiperidine.

Concentrated HCl solution is added to a solution of 6.4 g of thecompound obtained in the preceding step in 80 ml of MeOH until the pH=1,and the mixture is left stirring for 4 hours at RT. It is concentratedunder vacuum, the residue is extracted with DCM, the organic phase iswashed three times with 10% NaOH solution and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum. 3.2 g of the expected product are obtained after crystallizationin ether, m.p.=95° C.

PREPARATION 1.24.

4-(2-Hydroxyethyl)-4-phenylpiperidine.

A) 4-(Ethoxycarbonylmethyl)-4-phenylpiperidine.

A mixture of 16 g of the compound obtained in PREPARATION 1.22 and a fewdrops of H₂ SO₄ in 200 ml of EtOH is heated to reflux for 8 hours. Themixture is concentrated under vacuum, the residue is taken up in water,the aqueous phase is neutralized by adding Na₂ CO₃ and extracted withether, the organic phase is washed with water and dried over Na₂ SO₄ andthe solvent is evaporated off under vacuum. 7 g of the expected productare obtained.

B) 4-(Ethoxycarbonylmethyl)-4-phenyl-1-tritylpiperidine.

A solution of 7 g of the compound obtained in the preceding step and 5ml of triethylamine in 100 ml of DCM is cooled to 0° C., 8.9 g of tritylchloride are added slowly and the mixture is left stirring whileallowing the temperature to rise to RT. The mixture is concentratedunder vacuum, the residue is extracted with ether, the organic phase iswashed with water and with a pH 2 buffer solution and dried over Na₂ SO₄and the solvent is evaporated off under vacuum. 10 g of the expectedproduct are obtained after solidification in an iso ether/pentanemixture, m.p.=120° C.

C) 4-(2-Hydroxyethyl)-4-phenyl-1-tritylpiperidine.

A suspension of 1.5 g of lithium aluminium hydride in 50 ml of THF iscooled to 0° C., a solution of 10 g of the compound obtained in thepreceding step in 80 ml of THF is added slowly and the mixture is leftstirring while allowing the temperature to rise to RT. The mixture ishydrolysed by adding 10 ml of water dropwise, the inorganic salts arefiltered off and the filtrate is concentrated under vacuum. 8.5 g of theexpected product are obtained.

D) 4-(2-Hydroxyethyl)-4-phenylpiperidine.

A mixture of 8.5 g of the compound obtained in the preceding step, 40 mlof formic acid and 40 ml of water is heated to 60° C. for 1 hour. Theinsoluble matter is filtered off and the filtrate is concentrated undervacuum. The residue is taken up in water and neutralized by addingconcentrated NaOH solution, the mixture is extracted with DCM, theorganic phase is washed with water and dried over Na₂ SO₄ and thesolvents are evaporated off under vacuum. The residue is taken up inDCM, ethereal hydrogen chloride is added until the pH 1 and the solventsare evaporated off under vacuum. The residue is taken up in water, theaqueous phase is washed with ether, neutralized by adding concentratedNaOH and extracted with DCM, the organic phase is washed with water anddried over Na₂ SO₄ and the solvent is evaporated off under vacuum. 2.5 gof the expected product are obtained.

PREPARATION 1.25.

4-(2-Amino-4-thiazolyl)-4-phenylpiperidine p-toluenesulphonatemonohydrate.

A) 4-(2-Bromoacetyl)-4-phenylpiperidine hydrobromide.

8 g of bromine are added rapidly at RT to a suspension of 11.98 g of4-acetyl-4-phenylpiperidine hydrochloride in 200 ml of DCM, and thereaction mixture is left stirring overnight at RT. It is diluted byadding 200 ml of ether, and the precipitate formed is drained and washedwith ether. 17.88 g of the expected product are obtained after dryingunder vacuum.

B) 4-(2-Amino-4-thiazolyl)-4-phenylpiperidine p-toluenesulphonatemonohydrate.

A mixture of 7.26 g of the compound obtained in the preceding step and1.52 g of thiourea in 150 ml of EtOH is heated to reflux for 3 hours.The reaction mixture is concentrated under vacuum, the residue is takenup with water, the mixture is alkalinized to pH 13 by adding 10% NaOHsolution, and the precipitate formed is drained and washed with waterand then with ether. 4.46 g of the expected product are obtained in freebase form after recrystallization in EtOH. 1 g of the base is dissolvedin acetone, and 0.73 g of p-toluenesulphonic acid monohydrate is added.1.5 g of the crystallized expected product are obtained, m.p.=220-222°C.

PREPARATION 1.26.

4-[2-(Diethylamino)-4-thiazolyl]-4-phenylpiperidine p-toluenesulphonate.

A) 1,1-Diethylthiourea.

A solution of 10.67 g of potassium thiocyanate in 100 ml of acetone iscooled in an ice bath, a solution of 12.06 g of pivaloyl chloride in 30ml of acetone is added dropwise and the mixture is left stirring for 30minutes while allowing the temperature to rise to RT. The reactionmixture is cooled in an ice bath, a solution of 7.3 g of diethylamine in30 ml of acetone is added dropwise and the mixture is left stirringwhile allowing the temperature to rise to RT. The mixture isconcentrated under vacuum, the residue is taken up in ether, the organicphase is washed twice with water and with saturated NaCl solution anddried over MgSO₄ and the solvent is evaporated off under vacuum. Theproduct obtained is taken up in 50 ml of concentrated HCl solution andthe mixture is heated to 100° C. for 1 hour. After cooling to RT, themixture is washed twice with ether, the aqueous phase is alkalinized topH 9 by adding 30% NaOH solution and extracted three times with DCM, theorganic phase is washed twice with 10% NaOH solution and with saturatedNaCl solution and dried over MgSO₄ and the solvent is evaporated offunder vacuum. The residue is taken up in ether and the precipitateformed is drained. 9.44 g of the expected product are obtained.

B) 4-[2-(Diethylamino)-4-thiazolyl]-4-phenylpiperidinep-toluenesulphonate.

A mixture of 7.26 g of the compound obtained in step A of PREPARATION1.25 and 2.64 g of the compound obtained in the preceding step in 150 mlof EtOH is heated to reflux for 2 hours. The mixture is concentratedunder vacuum, the residue is taken up in water, the mixture isalkalinized to pH 12 by adding 10% NaOH solution and extracted twicewith ether, the organic phase is washed with 10% NaOH and with saturatedNaCl solution and dried over MgSO₄ and the solvent is evaporated offunder vacuum. 5.7 g of the product are obtained in free base form. Thebase is dissolved in acetone, a solution of 3.44 g of p-toluenesulphonicacid monohydrate in 10 ml of acetone is added dropwise and thecrystallized product formed is drained. 7.6 g of the expected productare obtained, m.p.=205-206° C.

PREPARATION 1.27.

4-[2-(Dimethylamino)-4-thiazolyl]-4-phenylpiperidinep-toluenesulphonate.

A) 1,1-Dimethylthiourea.

This compound is prepared according to the procedure described in step Aof PREPARATION 1.26, from 10.67 g of potassium thiocyanate, 12.06 g ofpivaloyl chloride and 4.51 g of dimethylamine. 6.7 g of the expectedproduct are obtained.

B) 4-[2-(Dimethylamino)-4-thiazolyl]-4-phenylpiperidinep-toluenesulphonate.

This compound is prepared according to the procedure described in step Bof PREPARATION 1.26, from 7.26 g of the compound obtained in step A ofPREPARATION 1.25 and 2.08 g of the compound obtained in the precedingstep in 150 ml of EtOH. 6.1 g of the expected product are obtained.

PREPARATION 1.28.

4-(2-Amino-1,3,4-oxadiazol-5-yl)-4-phenylpiperidine p-toluenesulphonate.

A) 1-(Benzyloxycarbonyl)-4-carboxy-4-phenylpiperidine.

A mixture of 37.7 g of 4-carboxy-4-phenylpiperidine p-toluenesulphonate,53.3 g of 30% aqueous NaOH solution and 250 ml of water is cooled to 5°C. A solution of 18 g of benzyl chloroformate in 60 ml of acetone isadded rapidly at 5° C., and the mixture is left stirring overnight whileallowing the temperature to rise to RT. The reaction mixture is washedtwice with ether and, after settling has taken place, the aqueous phaseis separated and acidified to pH 1 by adding concentrated HCl and then2N HCl. The precipitate formed is drained, dried, taken up in ether anddrained again. 30.6 g of the expected product are obtained,m.p.=142-144° C.

B) 1-(Benzyloxycarbonyl)-4-(chloroformyl)-4-phenylpiperidine.

A mixture of 17.1 g of the compound obtained in the preceding step and24 g of thionyl chloride in 150 ml of 1,2-dichloroethane is heated toref lux for 1 hour. It is concentrated under vacuum, the residue istaken up in chloroform and the solvent is evaporated off under vacuum.The residue is taken up in an ether/pentane mixture and the solvents areagain evaported off under vacuum. 20 g of the expected product areobtained in the form of a gum, which is used without further treatment.

C) 1-(Benzyloxycarbonyl)-4-carbazoyl-4-phenylpiperidine.

A solution of 16 g of hydrazine monohydrate in 40 ml of EtOH is cooledto -50° C., a solution of 11.44 g of the compound obtained in thepreceding step in 20 ml of 1,2-dimethoxyethane is added dropwise and themixture is left stirring while allowing the temperature to rise to RT.The mixture is concentrated under vacuum, the residue is taken up withwater, the product is extracted with DCM, the organic phase is washedwith water and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is taken up with anEtOH/benzene mixture and the solvents are evaporated off under vacuum.11.2 g of the expected product are obtained in the form of a gum, whichis used without further treatment.

D)4-(2-Amino-1,3,4-oxadiazol-5-yl)-1-(benzyloxycarbonyl)-4-phenylpiperidine.

A solution of 3.39 g of cyanogen bromide in 10 ml of EtOH is added at RTto a solution of 11.2 g of the compound obtained in the preceding stepin 60 ml of EtOH, and the reaction mixture is heated to ref lux for 1hour. It is concentrated to 50 ml of EtOH, and water is then addeddropwise until a volume of 400 ml of reaction mixture is obtained. Thecrystallized product formed is drained and washed with water and thenwith DCM, with AcOEt and with ether. 8 g of the expected product areobtained.

E) 4-(2-Amino-1,3,4-oxadiazol-5-yl)-4-phenylpiperidinep-toluenesulphonate.

A mixture of 7.85 g of the compound obtained in the preceding step, 3.95g of p-toluenesulphonic acid monohydrate, 0.8 g of palladium on charcoal(10% Pd), 350 ml of 95% EtOH and 10 ml of water is hydrogenated at 50°C. and at atmospheric pressure. After 3 hours, the catalyst is filteredoff on Celite® and the filtrate is concentrated under vacuum. Theresidue is taken up in acetone, and the crystallized product formed isdrained and washed with acetone and then with ether. 7.65 g of theexpected product are obtained, m.p.=183-185° C.

PREPARTION 1.29.

4-(3,3-Dimethylcarbazoyl)-4-phenylpiperidine p-toluenesulphonate.

A) 1-(Benzyloxycarbonyl)-4-(3,3-dimethylcarbazoyl)-4-phenylpiperidinep-toluenesulphonate.

A solution of 7.15 g of the compound obtained in step B of PREPARATION1.28 in 60 ml of DCM is cooled to 5° C., a solution of 1.44 g of1,1-dimethylhydrazine and 4.04 g of triethylamine in 20 ml of DCM isadded dropwise and the reaction mixture is left stirring overnight atRT. It is concentrated under vacuum, the residue is taken up with water,the product is extracted with AcOEt, the organic phase is washed withsaturated NaCl solution and dried over Na₂ SO₄ and the solvent isevaporated off under vacuum. The product obtained is dissolved in 100 mlof acetone, a solution of 3.59 g of p-toluenesulphonic acid in 10 ml ofacetone is added rapidly and the mixture is concentrated under vacuum.The residue is taken up in an ether/DCM mixture and the precipitateformed is drained. 9.65 g of the expected product are obtained.

B) 4-(3,3-Dimethylcarbazoyl)-4-phenylpiperidine p-toluene sulphonate.

A mixture of 9.5 g of the compound obtained in the preceding step and0.9 g of palladium on charcoal (10% Pd) in 100 ml of 95% EtOH ishydrogenated at 30° C. and at atmospheric pressure. The catalyst isfiltered off on Celite® and the filtrate is concentrated under vacuum.The residue is taken up in 100 ml of acetone, and the crystallizedproduct formed is drained and washed with ether. 7 g of the expectedproduct are obtained, m.p.=210-212° C.

PREPARATION 1.30.

4-(3-Ethyl-1-methylureido)-4-phenylpiperidine p-toluenesulphonate.

A) 1-Benzyl-4-(3-ethyl-1-methylureido)-4-phenylpiperidinep-toluenesulphonate.

A solution of 1.12 g of ethyl isocyanate in 5 ml of toluene is addeddropwise at RT to a solution of 4.2 g of the compound obtained in step Bof PREPARATION 1.4 in 25 ml of toluene, and the reaction mixture is leftstirring for 1 hour at RT. It is concentrated under vacuum, the productobtained is dissolved in acetone, a solution of 2.8 g ofp-toluenesulphonic acid in acetone is added dropwise and the mixture isleft for crystallization to take place. 7.4 g of the expected productare obtained after draining the crystals formed.

B) 4-(3-Ethyl-1-methylureido)-4-phenylpiperidine p-toluenesulphonate.

A mixture of 7.4 g of the compound obtained in the preceding step, 0.7 gof palladium on charcoal (10% Pd) in 200 ml of EtOH and 10 ml of wateris hydrogenated at 40° C. and at atmospheric pressure. The catalyst isfiltered off and the filtrate is concentrated under vacuum. The residueis taken up in acetone and the solvent is evaporated off under vacuum.5.5 g of the expected product are obtained after crystallization inAcOEt, m.p.=165-166° C.

PREPARATION 1.31

4-Amino-4-phenylpiperidine dibenzenesulphonate.

26.95 g of the compound obtained in step B of PREPARATION 1.3 aredissolved in 50 ml of water, the mixture is alkalinized to pH 12 byadding concentrated NaOH solution, the product is extracted with DCM,the organic phase is washed with saturated NaCl solution and dried overNa₂ SO₄ and the solvent is evaporated off under vacuum. The oil obtainedis taken up in 300 ml of EtOH, 25 g of benzenesulphonic acid and 2.2 gof palladium on charcoal (5% Pd) are added and the mixture is thenhydrogenated at 40° C. and at atmospheric pressure. The catalyst isfiltered off on Celite® and washed with MeOH and the filtrate isconcentrated under vacuum. The residue is taken up in acetone and theprecipitate formed is drained. 29.7 g of the expected product areobtained, m.p.=276-278° C.

PREPARATION 1.32

4-Benzyl-4-(ethoxycarbonylamino)piperidine p-toluene sulphonate.

A) 1,4-Dibenzyl-4-isocyanatopiperidine.

A mixture of 2 g of the compound obtained in step B of PREPARATION 1.11and 1.6 g of phosphorus pentachloride in 40 ml of chloroform is heatedto 60° C. for 1 hour. The reaction mixture is concentrated under vacuum,the residue is taken up in 40 ml of acetone, a solution of 2 g of sodiumazide in 5 ml of water is added and the mixture is left stirring for 30minutes at RT. It is concentrated under vacuum at RT, the residue istaken up in ether, the organic phase is washed with saturated Na₂ CO₃solution and with water and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is taken up in 40 ml of tolueneand the mixture is heated to reflux for 1 hour. It is concentrated undervacuum, and 2 g of the expected product are obtained in the form of anoil.

B) 1,4-Dibenzyl-4-(ethoxycarbonylamino)piperidine p-toluenesulphonate.

A mixture of 1 g of the compound obtained in the preceding step and 20ml of EtOH is heated to reflux for 24 hours. The mixture is concentratedunder vacuum, the oil obtained is dissolved in 5 ml of acetone, 0.55 gof para-toluenesulphonic acid monohydrate is added and ether is thenadded until crystallization takes place. The crystals formed aredrained, washed with ether and dried. 1.38 g of the expected product areobtained, m.p.=154° C.

C) 4-Benzyl-4-(ethoxycarbonylamino)piperidine p-toluenesulphonate.

A mixture of 1.3 g of the compound obtained in the preceding step, 0.15g of palladium on charcoal (10% Pd) and 20 ml of EtOH is left stirringfor 24 hours under a hydrogen atmosphere. The catalyst is filtered offand the filtrate is concentrated under vacuum. 1 g of the expectedproduct is obtained in the form of a foam.

PREPARATION 1.33

4-[N-(1-Pyrrolidinyl)carbamoyl]-4-phenylpiperidine benzenesulphonate.

A)1-(benzyloxycarbonyl)-4-[N-(1-pyrrolidinyl)-carbamoyl]-4-phenylpiperidinebenzenesulphonate.

A mixture of 11.54 g of the compound obtained in step A of PREPARATION1.28 in 100 ml of 1,2-dichloroethane is heated to reflux, 16.18 g ofthionyl chloride are added, refluxing is continued for 1 hour and themixture is left stirring overnight at RT. It is concentrated undervacuum, the residue is taken up in 20 ml of DCM, the mixture is cooledto 5° C., 10.3 g of triethylamine and then 5 g of 1-aminopyrrolidinehydrochloride are added and the mixture is left stirring for 1 hour. Itis concentrated under vacuum, the residue is extracted with AcOEt, theorganic phase is washed with water and with saturated NaCl solution anddried over MgSO₄ and the solvent is evaporated off under vacuum. Theresidue is dissolved in acetone, ether is added until precipitationtakes place and the precipitate formed is drained. The precipitate isdissolved in EtOH, 2.61 g of benzenesulphonic acid are added and theprecipitate formed is drained. 9.34 g of the expected product areobtained.

B) 4-[N-(1-Pyrrolidinyl)carbamoyl]-4-phenylpiperidine benzenesulphonate.

A mixture of 9.34 g of the compound obtained in the preceding step and 1g of palladium on charcoal (5% Pd) in 200 ml of EtOH is hydrogenated for3 hours at 40° C. and at atmospheric pressure. The catalyst is filteredoff and the filtrate is concentrated under vacuum. 6.13 g of theexpected product are obtained after crystallization in an EtOH/acetonemixture.

PREPARATION 1.34

4-(3-Acetylcarbazoyl)-4-phenylpiperidine benzenesulphonate.

A) 1-(Benzyloxycarbonyl)-4-(3-acetylcarbazoyl)-4-phenylpiperidine.

A mixture of 25.44 g of the compound obtained in step A of PREPARATION1.28 and 35.7 g of thionyl chloride in 150 ml of 1,2-dichloroethane isheated to reflux for 2 hours and then concentrated under vacuum. Theproduct obtained is dissolved in 200 ml of chloroform, the mixture iscooled to 5° C., 12.22 g of 1-acetylhydrazine are added and the mixtureis left stirring while allowing the temperature to rise to RT. Themixture is concentrated under vacuum, the residue is taken up with 2NHCl solution, the mixture is extracted with AcOEt, and the precipitateformed is drained and washed with a DCM/AcOEt mixture: a first crop ofthe expected product is thereby obtained. After settling of the filtrateobtained above has taken place, the organic phase is separated andwashed with 2N HCl solution and with saturated NaCl solution and driedover Na₂ SO₄ and the solvents are evaporated off under vacuum. Theresidue is dissolved in AcOEt at 80° C. and, after cooling, ether isadded, the precipitate formed is drained and a second crop of theexpected product is obtained. A total of 23.06 g of the expected productis obtained.

B) 4-(3-Acetylcarbazoyl)-4-phenylpiperidine benzenesulphonate.

This compound is prepared according to the procedure described in step Bof PREPARATION 1.33, from 2.61 g of the compound obtained in thepreceding step, 1.04 g of benzenesulphonic acid, 0.3 g of palladium oncharcoal (5% Pd) and 70 ml of EtOH. 2.39 g of the expected product areobtained after crystallization in an EtOH/ether mixture.

PREPARATION 1.35.

4-(2-Methyl-1,3,4-oxadiazol-5-yl)-4-phenylpiperidine benzenesulphonate.

A)1-(Benzyloxycarbonyl)-4-(2-methyl-1,3,4-oxadiazol-5-yl)-4-phenylpiperidine.

A mixture of 22.3 g of the compound obtained in step A of PREPARATION1.34 and 0.75 g of p-toluenesulphonic acid monohydrate in 300 ml oftoluene is heated to reflux for 8 hours. The mixture is concentratedunder vacuum, the residue is taken up with 5% NaHCO₃ solution, theproduct is extracted with AcOEt, the organic phase is washed with waterand with saturated NaCl solution and dried over Na₂ SO₄ and the solventis evaporated off under vacuum. The residue is taken up in hot AcOEt,some insoluble matter is filtered off, the filtrate is left overnight atRT and diluted with ether and the precipitate formed is drained. 15.24 gof the expected product are obtained.

B) 4-(2-Methyl-1,3,4-oxadiazol-5-yl)-4-phenylpiperidinebenzenesulphonate.

A mixture of 13.2 g of the compound obtained in the preceding step, 5.53g of benzenesulphonic acid and 1.3 g of palladium on charcoal (5% Pd) in300 ml of EtOH is hydrogenated at 40° C. and at atmospheric pressure.The catalyst is filtered off and the filtrate is concentrated undervacuum. 13.5 g of the expected product are obtained aftercrystallization in an acetone/AcOEt/ether mixture.

PREPARATION 2.1.

2-(3,4-Dichlorophenyl)-4-hydroxybutylamine, (+) isomer.

The preparation of this compound is described in Patent ApplicationEP-A-0612716.

PREPARATION 2.2.

2-(3,4-Dichlorophenyl)-4-(tetrahydro-2-pyranyloxy)-butylamine.

A) 2-(3,4-Dichlorophenyl)-4-(tetrahydro-2-pyranyloxy)-butanenitrile.

A solution of 100 g of 3,4-dichlorophenylacetonitrile in 500 ml of THFis added dropwise at 20° C. over 30 minutes to a suspension of 16.5 g ofsodium hydride in 200 ml of dry THF, and the reaction mixture is thenstirred at RT for 2 hours. It is cooled to -20° C., a solution of 118 gof 1-bromo-2-(tetrahydro-2-pyranyloxy)ethane in 100 ml of THF is addedand the mixture is left stirring for 2 hours while allowing thetemperature to rise to RT. A solution of 50 g of ammonium chloride in 3litres of water is then added, the product is extracted with 1.5 litresof ether, and the organic phase is washed with saturated sodium chloridesolution, dried over magnesium sulphate and evaporated under vacuum. Theresidue is chromatographed on silica, eluting with DCM and then with aDCM/AcOEt (95:5; v/v) mixture. 118 g of the expected product areobtained in the form of an oil.

B) 2-(3,4-Dichlorophenyl)-4-(tetrahydro-2-pyranyloxy)-butylamine.

300 ml of concentrated aqueous ammonia are added to a solution of 118 gof nitrile obtained above in 700 ml of absolute EtOH, and Raney® nickel(10% of the amount of starting nitrile) is then introduced under anitrogen atmosphere. The mixture is thereafter hydrogenated at RT andunder pressure from a column of water. The catalyst is filtered off onCelite® and the filtrate is evaporated under vacuum. The residue istaken up with saturated sodium chloride solution, the product isextracted with ether, the organic phase is dried over magnesium sulphateand the solvent is evaporated off under vacuum. 112 g of the expectedproduct are obtained in the form of an oil.

PREPARATION 2.3.

N-Methyl-2-(3,4-dichlorophenyl)-4-tetrahydro-2-pyranyloxy)butylaminehydrochloride.

A) 2-(3,4-Dichlorophenyl)-4-hydroxybutylamine.

80 ml of a saturated solution of hydrochloric acid in ether are added toa solution of 81 g of the compound obtained in step B of PREPARATION 2.2in 38 ml of MeOH while the temperature is maintained at between 20 and25° C. The reaction mixture is left stirring at RT for 30 minutes andevaporated under vacuum. The residue is dissolved in 250 ml of water,the mixture is washed twice with ether, the aqueous phase is alkanilizedby adding 1N NaOH solution, the product is extracted with DCM, theorganic phase is dried over magnesium sulphate and the solvent isevaporated off under vacuum. The residue is taken up in 800 ml of isoether, the insoluble matter is filtered off on Celite and the filtrateis concentrated under vacuum to approximately 300 ml. The solution isinoculated with crystals of the expected amino alcohol and stirredovernight, and the precipitate formed is filtered off and washed withiso ether and then with n-pentane. 30.2 g of the expected product areobtained, m.p.=90-91° C.

B) N-tert-Butoxycarbonyl-2-(3,4-dichlorophenyl)-4-hydroxybutylamine.

A solution of 48.96 g of di-tert-butyldicarbonate in 100 ml of AcOEt isadded dropwise to a suspension of 50 g of the compound obtained in thepreceding step in 250 ml of AcOEt, and the reaction mixture is heated toreflux for 30 minutes. It is washed twice with pH 2 buffer, with waterand with saturated sodium chloride solution and dried over magnesiumsulphate and the solvent is evaporated off under vacuum. 72.79 g of theexpected product are obtained in the form of an oil, which crystallizesin hexane.

C) N-Methyl-2-(3,4-dichlorophenyl)-4-hydroxybutylamine hydrochloride.

A solution of 21.99 g of the compound obtained in the preceding step in150 ml of THF is added dropwise to a suspension of 10 g of lithiumaluminium hydride in 150 ml of anhydrous THF, and the reaction mixtureis heated to reflux for 7 hours. It is then diluted with 300 ml of THF,10 ml of water, 10 ml of 4N NaOH solution and 30 ml of water are addedslowly and the mixture is left stirring for 1 hour. The inorganic saltsare filtered off on Celite®, the filtrate is allowed to settle and theorganic phase is separated and evaporated under vacuum. The residue istaken up in acetone, a saturated solution of hydrochloric acid in etheris added to pH 1, the mixture is left stirring for 1 hour, and thecrystals formed are filtered off and washed with acetone and then withether. 13.49 g of the expected product are obtained, m.p.=149° C.

D) N-Methyl-2-(3,4-dichlorophenyl)4-(tetrahydro-2-pyranyloxy)butylaminehydrochloride.

A mixture of 13.04 g of the compound obtained in the preceding step,5.78 g of 3,4-dihydro-2H-pyran in 200 ml of DCM and a few drops of asaturated solution of hydrochloric acid in ether is heated to reflux for2 hours. After cooling, the reaction mixture is evaporated under vacuumand the residue is recrystallized in the heated state in acetone. 10.66g of the expected product are obtained, which is used without furthertreatment.

PREPARATION 2.4.

2-(3,4-Difluorophenyl)-4-(tetrahydro-2-pyranyloxy)butylamine.

A) 2-(3,4-Difluorophenyl)-4-(tetrahydro-2-pyranyloxy)butanenitrile.

A solution of 50 g of 3,4-difluorophenyl acetonitrile in 50 ml of THF isadded dropwise at 20° C. to a suspension of 14.4 g of 60% sodium hydridein oil in 250 ml of THF, and the reaction mixture is left tirring forthree hours at RT. It is cooled in an ice bath, a solution of 68.2 g of1-bromo-2-(tetrahydro-2-pyranyloxy)ethane in 50 ml of THF is addeddropwise and the reaction mixture is left stirring overnight at RT. Itis acidified by adding a pH 2 buffer solution, and the THF is thenevaporated off under vacuum. The aqueous phase is extracted with ether,the organic phase is washed twice with a pH 4 buffer solution, withwater and with saturated NaCl solution and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica, eluting with toluene and then with a toluene/AcOEt (100:3;v/v) mixture. 50 g of the expected product are obtained.

B) 2-(3,4-Difluorophenyl)-4-(tetrahydro-2-pyranyloxy)butylamine.

A mixture of 20.7 g of the compound obtained in the preceding step, 2.1g of Raney® nickel in 200 ml of EtOH and 50 ml of 20% aqueous ammoniasolution is hydrogenated at 30° C. and at atmospheric pressure. Thecatalyst is filtered off on Celite® and the fitrate is concentratedunder vacuum. The residue is extracted with ether, the organic phase iswashed with water and with saturated NaCl solution and dried over MgSO₄and the solvent is evaporated off under vacuum. 19 g of the expectedproduct are obtained.

PREPARATION 2.5.

5-(3,4-Difluorophenyl)-5-[2-(tetrahydro-2-pyranyloxy)ethyl]-2-piperidone.

A) Methyl4-cyano-4-(3,4-difluorophenyl)-6-(tetrahydro-2-pyranyloxy)hexanoate.

A mixture of 28.12 g of the compound obtained in step A of PREPARATION2.4 and 1 ml of Triton® B in 100 ml of THF is heated to ref lux, and asolution of 9.46 g of methyl acrylate in 10 ml of THF is added dropwise.After cooling to RT, the reaction mixture is concentrated under vacuum,the residue is taken up in water, the product is extracted with ether,the organic phase is washed with water, with a pH 4 buffer solution andwith saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. 35 g of the expected product are obtainedin the form of a red oil.

B)5-(3,4-Difluorophenyl)-5-[2-(tetrahydro-2-pyranyloxy)ethyl]-2-piperidone.

A mixture of 35 g of the compound obtained in the preceding step, 3.5 gof Raney® nickel and 5 g of KHCO₃ in 600 ml of 95% ethanol ishydrogenated in a Parr apparatus at 50° C. and at 20.4 bars pressure.The catalyst is filtered off on Celite® and the filtrate is concentratedunder vacuum. The residue is extracted with AcOEt, the organic phase iswashed twice with water and twice with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum. 32.1 g of theexpected product are obtained in the form of a yellow oil.

PREPARATION 2.6.

3-(3,4-Dichlorophenyl)-3-[2-(tetrahydro-2-pyranyloxy)ethyl]piperidine.

A) Ethyl4-cyano-4-(3,4-dichlorophenyl)-6-(tetrahydro-2-pyranyloxy)hexanoate.

A solution of 44.7 ml of a 1.5M solution of lithium diisopropylamide/THFcomplex in cyclohexane diluted in 100 ml of THF is added dropwise at RTto a solution of 21 g of the compound obtained in step A of PREPARATION2.2 in 100 ml of THF, and the mixture is left stirring for 1 hour at RT.12 g of ethyl 3-bromopropionate are then added and the reaction mixtureis heated to 50° C. for 2 hours. After cooling, it is poured intosaturated ammonium chloride solution, the product is extracted withether, the organic phase is washed with water and dried over sodiumsulphate and the solvent is evaporated off under vacuum. The residue ischromatographed on silica, eluting with a DCM/AcOEt (100:1; v/v)mixture. 13 g of the expected product are obtained, which is used in thenext step without further treatment.

B)5-(3,4-Dichlorophenyl)-5-[2-(tetrahydro-2-pyranyloxy)ethyl]-2-piperidone.

40 ml of concentrated aqueous ammonia are added to solution of 13 g ofthe compound obtained in the receding step in 250 ml of EtOH, and Raney®nickel (10% of the amount of starting nitrile) is then introduced. Themixture is thereafter hydrogenated at RT and at atmospheric pressure.The catalyst is filtered off on Celite® and the filtrate is evaporatedunder vacuum. The residue is taken up in water, the product is extractedwith ether, the organic phase is washed with water and dried overmagnesium sulphate and the solvent is evaporated off under vacuum. 9 gof the expected product are obtained, which is used in the next stepwithout further treatment.

C)3-(3,4-Dichlorophenyl)-3-[2-(tetrahydro-2-pyranyloxy)ethyl]piperidine.

A suspension of 0.9 g of lithium aluminium hydride in 5 ml of THF isheated to 60° C., a solution of 3.9 g of the compound obtained in thepreceding step in 50 ml of THF is added and the mixture is left stirringfor 1 hour at 60° C. After cooling, 1 ml of water, 1 ml of 4N NaOH and 3ml of water are added. The inorganic salts are filtered off on Celite®,the filtrate is allowed to settle and the organic phase is separated andevaporated under vacuum. The residue is taken up in ether, the organicphase is dried over magnesium sulphate and the solvent is evaporated offunder vacuum. 3.4 g of the expected product are obtained, which is usedwithout further treatment.

PREPARATION 2.7

3-(3,4-Dichlorophenyl)-3-(2-hydroxyethyl)piperidine, (-) isomer.

The preparation of this compound is described in Patent ApplicationEP-A-0591040.

EXAMPLE 1

N-[2-(3,4-Dichlorophenyl)-4-[4-(2-hydroxyethoxy)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride monohydrate, (-) isomer.

A) N-[2-(3,4-Dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide, (-)isomer.

The preparation of this compound is described in Patent ApplicationEP-A-0474561, from the compound obtained in PREPARATION 2.1.

B)N-[4-(Benzenesulphonyloxy)-2-(3,4-dichlorophenyl)-butyl]-N-methylbenzamide,(-) isomer.

5 g of benzenesulphonyl chloride are added to a mixture of 5 g of thecompound obtained in the preceding step and 3.54 g of triethylamine in30 ml of DCM, and the mixture is left stirring for 3 hours 30 minutes atRT. A further 0.5 g of benzenesulphonyl chloride is added and stirringis continued for 1 hour 30 minutes. 30 ml of water are added to thereaction mixture, settling is allowed to take place, the organic phaseis separated and washed twice with 30 ml of IN HCl solution and with 30ml of water and dried over MgSO₄ and the solvent is evaporated off undervacuum. The oil obtained is taken up in 50 ml of tert-butyl methyl etherand the mixture is left stirring overnight. 4.33 g of the expectedproduct are obtained after draining and drying the white precipitateobtained, m.p.=93° C.

[α]_(D) ²⁰ =-13.0° (c=1; MeOH).

C)N-[2-(3,4-Dichlorophenyl)-4-[4-(2-hydroxyethoxy)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride monohydrate, (-) isomer.

A mixture of 2.75 g of the compound obtained in the preceding step, 1.7g of the compound obtained in PREPARATION 1.1 and 1.8 g of K₂ CO₃ in 20ml of DMF is heated to 80° C. for 2 hours. After cooling to RT, thereaction mixture is poured into water, the product is extracted withAcOEt, the organic phase is washed three times with water and dried overMgSO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica, eluting with DCM and then with a DCM/MeOH(97:3; v/v) mixture. The product obtained is dissolved in DCM, themixture is acidified to pH 1 by adding ethereal hydrogen chloride andthe precipitate formed is drained. 1.9 g of the expected product areobtained, m.p.=133-135° C.

[α]_(D) ²⁰ =-20.0° (c=1; MeOH).

EXAMPLE 2

N-[4-[4-(2-Acetoxyethoxy)-4-phenyl-1-piperidyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamidehydrochloride hemihydrate, (-) isomer.

A solution of 0.6 g of the compound obtained in EXAMPLE 1 and 0.3 ml oftriethylamine in 20 ml of DCM is cooled to 0-5° C., 0.08 ml of acetylchloride is added and the mixture is left stirring while the temperatureis allowed to rise to RT. The reaction mixture is concentrated undervacuum and the residue is chromatographed on silica, eluting with DCMand then with a DCM/MeOH (97:3; v/v) mixture. The product obtained isdissolved in DCM, the mixture is acidified to pH 1 by adding etherealhydrogen chloride and the precipitate formed is drained. 0.23 g of theexpected product is obtained, m.p.=95° C.

[α]_(D) ²⁰ =-30.4° (c=1; MeOH).

EXAMPLE 3

N-[2-(3,4-Dichlorophenyl)-4-[4-(2-methoxyethoxy)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride 0.6 hydrate, (-) isomer.

This compound is prepared according to the procedure described in step Cof EXAMPLE 1, from 0.5 g of the compound obtained in PREPARATION 1.2,0.85 g of the compound obtained in step B of EXAMPLE 1 and 0.35 g of K₂CO₃ in 5 ml of DMF. 0.35 g of the expected product is obtained,m.p.=76-78° C.

[α]_(D) ²⁰ =-32.6° (c=1; MeOH).

EXAMPLE 4

N-[4-[4-(Acetyl-N-methylamino)-4-phenyl-1-piperidyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamidehydrochloride monohydrate, (-) isomer.

A mixture of 1.67 g of the compound obtained in step B of EXAMPLE 1 and1.5 g of K₂ CO₃ in 10 ml of a DMF/acetonitrile (50:50; v/v) mixture isheated to 80° C., 1.9 g of the compound obtained in PREPARATION 1.4 areadded slowly and heating is continued at 80° C. for 2 hours. Aftercooling, the reaction mixture is poured into water, the product isextracted with AcOEt, the organic phase is washed twice with water andwith saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is chromatographed on silica H,eluting with a DCM/MeOH mixture from (98:2; v/v) to (95:5; v/v). Theproduct obtained is dissolved in AcOEt, ethereal hydrogen chloride isadded until the pH=1 and ether is then added until precipitation takesplace. 1.14 g of the expected product are obtained after draining anddrying, m.p.=137-139° C. [α]_(D) ²⁰ =-34.0° (c=0,5; MeOH).

EXAMPLE 5

N-[2-(3,4-Dichlorophenyl)-4-[4-(methoxycarbonylamino)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride hemihydrate, (-) isomer.

A mixture of 1.97 g of the compound obtained in step B of EXAMPLE 1,1.95 g of the compound obtained in PREPARATION 1.5 and 1.99 g of K₂ CO₃in 16 ml of a DMF/acetonitrile (50:50; v/v) mixture is heated to 100° C.for 3 hours. After cooling to RT, the reaction mixture is poured into250 ml of water, the product is extracted three times with AcOEt, theorganic phase is washed with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica, eluting with DCM and then with DCM/MeOH(96:4; v/v) mixture. The product obtained is dissolved in AcOEt, astream of HCl gas is bubbled through until the pH=1 and ether is thenadded until precipitation takes place. 1.44 g of the expected productare obtained, m.p.=149° C.

[α]_(D) ²⁰ =-32.8° (c=0.5; MeOH).

EXAMPLE 6

N-[2-(3,4-Dichlorophenyl)-4-[4-(ethoxycarbonyl-amino)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride hemihydrate, (-) isomer.

This compound is prepared according to the procedure described inEXAMPLE 5, from 1.72 g of the compound obtained in step B of EXAMPLE 1,1.52 g of the compound obtained in PREPARATION 1.6, 1.74 g of K₂ CO₃ and16 ml of a DMF/acetonitrile (50:50; v/v) mixture. 1.1 g of the expectedproduct are obtained, m.p.=125° C.

[α]_(D) ²⁰ =-28.8° (c=0.5; MeOH).

EXAMPLE 7

N-[2-(3,4-Dichlorophenyl)-4-[4-(methanesulphonamido)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride, (-) isomer.

This compound is prepared according to the procedure described inEXAMPLE 5, from 1.71 g of the compound obtained in step B of EXAMPLE 1,1.90 g of the compound obtained in PREPARATION 1.7, 1.53 g of K₂ CO₃ and10 ml of a DMF/acetonitrile (50:50; v/v) mixture. 1.28 g of the expectedproduct are obtained after crystallization in an acetone/ether mixture,m.p.=245° C.

[α]_(D) ²⁰ =-33° (c=0.5; MeOH).

EXAMPLE 8

N-[2-(3,4-Dichlorophenyl)-4-[4-(3-ethylureido)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride hemihydrate, (-) isomer.

This compound is prepared according to the procedure described inEXAMPLE 5, from 1.72 g of the compound obtained in step B of EXAMPLE 1,1.76 g of the compound obtained in PREPARATION 1.8, 1.74 g of K₂ CO₃ and16 ml of a DMF/acetonitrile (50:50; v/v) mixture. 1.13 g of the expectedproduct are obtained, m.p.=135° C.

[α]_(D) ²⁰ =-30.4° (c=0.5; MeOH).

EXAMPLE 9

N-[2-(3,4-Dichlorophenyl)-4-[4-(3-cyclopentylureido)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride monohydrate, (-) isomer.

This compound is prepared according to the procedure described inEXAMPLE 5, from 1.72 g of the compound obtained in step B of EXAMPLE 1,1.93 g of the compound obtained in PREPARATION 1.9, 1.74 g of K₂ CO₃ and16 ml of a DMF/acetonitrile (50:50; v/v) mixture. 1.3 g of the expectedproduct are obtained, m.p.=150° C.

[α]_(D) ²⁰ =-24.6° (c=0.5; MeOH).

EXAMPLE 10

N-[2-(3,4-Dichlorophenyl)-4-[4-(3,3-dimethylureido)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride hemihydrate, (-) isomer.

This compound is prepared according to the procedure described inEXAMPLE 5, from 1.46 g of the compound obtained in step B of EXAMPLE 1,1.6 g of the compound obtained in PREPARATION 1.10, 1.31 g of K₂ CO₃ and16 ml of a DMF/acetonitrile (50:50; v/v) mixture. After chromatography,the product obtained is dissolved in AcOEt, ethereal hydrogen chlorideis added until the pH=1 and the crystallized product formed is drained.0.72 g of the expected product is obtained, m.p. 175-177° C.

[α]_(D) ²⁰ =-26.8° (c=0.5; MeOH).

EXAMPLE 11

N-[4-[4-Benzyl-4-(3,3-dimethylureido)-1-piperidyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamidehydrochloride, (-) isomer.

A mixture of 0.5 g of the compound obtained in step B of EXAMPLE 1, 0.54g of the compound obtained in PREPARATION 1.11 and 0.52 g of K₂ CO₃ in 5ml of DMF is heated to 90° C. for 2 hours 30 minutes. The reactionmixture is poured into ice-cold water, the product is extracted withAcOEt, the organic phase is washed with 1N NaOH solution and withsaturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is chromatographed on silica H,eluting with DCM and then with a DCM/MeOH (93:7; v/v) mixture. Theproduct obtained is taken up in ethereal hydrogen chloride and theprecipitate formed is drained. 0.45 g of the expected product isobtained, m.p.=155° C. (dec.).

[α]_(D) ²⁰ =-18.4° (c=0.5; MeOH).

EXAMPLE 12

N-[2-(3,4-(Dichlorophenyl)-4-[4-(3,3-diethylureido)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride sesquihydrate, (-) isomer.

This compound is prepared according to the procedure described inEXAMPLE 5, from 1.72 g of the compound obtained in step B of EXAMPLE 1,1.88 g of the compound obtained in PREPARATION 1.12, 1.74 g of K₂ CO₃and 16 ml of a DMF/acetonitrile (50:50; v/v) mixture. 0.92 g of theexpected product is obtained, m.p.=131° C.

[α]_(D) ²⁰ =-22.8° (c=0.5; MeOH).

EXAMPLE 13

N-[2-(3,4-Dichlorophenyl)-4-[4-(phenyl)-4-(1-pyrrolidinylcarbonylamino)-1-piperidyl]butyl]-N-methylbenzamidehydrochloride-hemihydrate, (-) isomer.

A mixture of 1.72 g of the compound obtained in step B of EXAMPLE 1,1.86 g of the compound obtained in PREPARATION 1.13 and 1.72 g of K₂ CO₃in 16 ml of a DMF/acetonitrile (50:50; v/v) mixture is heated to 100° C.for 1 hour, and the reaction mixture is then left stirring overnight atRT. It is poured into 250 ml of water, and the crystallized productformed is drained and dried. The product is chromatographed on silica,eluting with a DCM/MeOH mixture from (98:2; v/v) to (96:4; v/v). Theproduct obtained is dissolved in AcOEt, a stream of HCl gas is bubbledthrough until the pH=1 and the precipitate formed is drained. 1.27 g ofthe expected product are obtained, m.p.=178-180° C.

[α]_(D) ²⁰ =-24.4° (c=0.5; MeOH).

EXAMPLE 14

N-[2-(3,4-Dichlorophenyl)-4-[4-(N-methylcarbamoyl)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride dihydrate, (-) isomer.

This compound is prepared according to the procedure described inEXAMPLE 5, from 1.25 g of the compound obtained in step B of EXAMPLE 1,0.71 g of the compound obtained in PREPARATION 1.14 and 0.75 g of K₂ CO₃in 10 ml of a DMF/acetonitrile (50:50; v/v) mixture. 0.23 g of theexpected product is obtained, m.p.=100-102° C.

[α]_(D) ²⁰ =-31.2° (c=0.5; MeOH).

EXAMPLE 15

N-[2-(3,4-Dichlorophenyl)-4-[4-(ethylaminocarbonyloxymethyl)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride sesquihydrate.

A) N-[2-(3,4-Dichlorophenyl)-4-(tetrahydro-2-pyranyloxy)butyl]benzamide.

4.42 g of benzoyl chloride in 20 ml of DCM is added dropwise to asolution of 9.54 g of the compound obtained in PREPARATION 2.2 and 3.33g of triethylamine in 50 ml of DCM, and the reaction mixture is leftstirring for 1 hour at RT and then heated to reflux for 1 hour. It isconcentrated under vacuum, the residue is taken up in water, the productis extracted with ether, the organic phase is washed with water, with 5%NaOH solution and with saturated NaCl solution and dried over Na₂ SO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on silica, eluting with a DCM/MeOH (98:2; v/v) mixture.8.3 g of the expected product are obtained in the form of an oil.

B) N-[2-(3,4-Dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide.

0.54 g of 55% sodium hydride in oil is added portionwise to a solutionof 3.8 g of the compound obtained in the preceding step in 40 ml of THF,and the mixture is left stirring for 20 minutes at RT. 1.4 g of methyliodide are then added dropwise and the reaction mixture is left stirringovernight at RT. It is concentrated under vacuum, the residue is takenup in water, the product is extracted with ether, the organic phase iswashed with water and with saturated NaCl solution and dried over Na₂SO₄ and the solvent is evaporated off under vacuum. The oil obtained isdissolved in 30 ml of MeOH, 0.3 g of Amberlyst H-15 is added and themixture is heated to reflux for 1 hour. The resin is filtered off onCelite and the filtrate is concentrated under vacuum. 2.67 g of theexpected product are obtained after solidification in ether,m.p.=137-139° C.

C)N-[2-(3,4-Dichlorophenyl)-4-(methanesulphonyloxy)butyl]-N-methylbenzamide.

A solution of 5.26 g of methanesulphonyl chloride in 20 ml of DCM isadded dropwise to a solution of 14.72 g of the compound obtained in thepreceding step and 5.05 g of triethylamine in 150 ml of DCM, and thereaction mixture is left stirring for 1 hour at RT. It is concentratedunder vacuum, the residue is taken up in water, the product is extractedwith AcOEt, the organic phase is washed with saturated NaCl solution anddried over Na₂ SO₄ and the solvent is evaporated off under vacuum. 16.24g of the expected product are obtained after crystallization in ether,m.p.=100-102° C.

D)N-[2-(3,4-Dichlorophenyl)-4-[4-(ethylaminocarbonyloxymethyl)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride sesquihydrate.

A mixture of 0.23 g of the compound obtained in the preceding step, 0.17g of the compound obtained in PREPARATION 1.15 and 0.22 g of K₂ CO₃ in10 ml of a DMF/acetonitrile (50:50; v/v) mixture is heated to 100° C.for 3 hours. The reaction mixture is concentrated under vacuum, theresidue is taken up in water, the product is extracted with AcOEt, theorganic phase is washed with water and with saturated NaCl solution anddried over MgSO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica H, eluting with DCM and then with aDCM/MeOH (96:4; v/v) mixture. The product obtained is dissolved inAcOEt, a stream of HCl gas is bubbled through until the pH=1, ether isthen added and the mixture is concentrated under vacuum. 0.05 g of theexpected product is obtained, m.p.=70-72-C.

EXAMPLE 16

N-[2-(3,4-Dichlorophenyl)-4-[4-(formylamino)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride hemihydrate.

0.55 g of the compound obtained in PREPARATION 1.3 is dissolved inwater, the mixture is alkalinized by adding concentrated NaOH solution,the product is extracted with DCM, the organic phase is dried over MgSO₄and the solvent is evaporated off under vacuum. The product obtained istaken up in 20 ml of acetonitrile, 0.85 g of the compound obtained instep C of EXAMPLE 15 and 1 g of K₂ CO₃ are added and the reactionmixture is heated to reflux for 2 hours 30 minutes. It is concentratedunder vacuum, the residue is extracted with AcOEt, the organic phase iswashed with water and with 5% NaOH solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H, eluting with DCM and then with a DCM/MeOH (90:10; v/v)mixture. The product obtained is taken up in ethereal hydrogen chlorideand the precipitate formed is drained. 0.51 g of the expected product isobtained.

Proton NMR spectrum at 200 MHz in DMSO-d₆.

δ: 1.8 to 2.65 ppm: uc: 6 H

2.65 to 3.9 ppm: uc: 12 H

6.8 to 7.9 ppm: uc: 13 H

8.1 ppm: s: 1 H

8.45 ppm: s: 1 H

10.95 ppm: S: 1 H

EXAMPLE 17

N-[4-[4-(Acryloyl-N-methylamino]-4-phenyl-1-piperidyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamidehydrochloride sesquihydrate.

A mixture of 0.5 g of the compound obtained in step C of EXAMPLE 15,0.36 g of the compound obtained in PREPARATION 1.16 and 0.35 g of K₂ CO₃in 5 ml of DMF is heated to 80° C. for 2 hours. The reaction mixture ispoured into water, the product is extracted with AcOEt, the organicphase is washed twice with water and with saturated NaCl solution anddried over MgSO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica, eluting with a DCM/MeOH mixturefrom (99:1; v/v) to (95:5; v/v). The product obtained is dissolved inDCM, the mixture is acidified to pH 1 by adding ethereal hydrogenchloride and the precipitate formed is drained. 0.25 g of the expectedproduct is obtained, m.p.=120° C.

EXAMPLE 18

N-[4-[4-(Carboxymethyl)-4-phenyl-1-piperidyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamidehydrochloride sesquihydrate.

1.8 g of potassium tert-butylate and then 1.5 g of the compound obtainedin step C of EXAMPLE 15 are added to a solution of 2.3 g of the compoundobtained in PREPARATION 1.22 in 20 ml of DMF, and the reaction mixtureis heated to 80° C. for 2 hours. It is concentrated under vacuum, theresidue is taken up in water, the mixture is neutralized to pH 7 byadding concentrated HCl solution, the product is extracted with DCM, theorganic phase is washed with water and dried over MgSO₄ and the solventis evaporated off under vacuum. The residue is chromatographed on silicaH, eluting with a DCM/MeOH (95:5; v/v) mixture. The product obtained istaken up with ethereal hydrogen chloride and the solvent is evaporatedoff under vacuum. 0.96 g of the expected product is obtained aftercrystallization in iso ether.

Proton NMR spectrum at 200 MHz in DMSO-d₆.

δ: 1.2 to 2.45 ppm: uc: 6 H

2.5 to 3.8 ppm: uc: 14 H

6.6 to 7.6 ppm: uc: 13 H.

EXAMPLE 19

N-[4-[4-(Carboxymethyl)-4-phenyl-1-piperidyl]-2-(3,4-dichlorophenyl)butyl]-N-methyl-2-(3-isopropoxyphenyl)acetamidehydrochloride.

A)N-[2-(3,4-Dichlorophenyl)-4-(tetrahydro-2-pyranyloxy)butyl]-N-methyl-2-(3-isopropoxyphenyl)acetamide.

8.78 g of triethylamine and then 5.62 g of 3-isopropoxyphenylacetic acidand 14.11 g of BOP are added to a solution of 10.66 g of the compoundobtained in PREPARATION 2.3 in 100 ml of DCM. The reaction mixture isleft stirring for 4 hours at RT and concentrated under vacuum. Theresidue is extracted with AcOEt, the mixture is washed with water, with10% NaOH solution, with water and with saturated sodium chloridesolution and dried over magnesium sulphate and the solvent is evaporatedoff under vacuum. The residue is chromatographed on silica, eluting witha DCM/MeOH (90:10; v/v) mixture. 13.40 g of the expected product areobtained, which is used in the next step without further treatment.

B)N-[2-(3,4-Dichlorophenyl)-4-hydroxybutyl]-N-methyl-2-(3-isopropoxyphenyl)acetamide.

A few drops of a saturated solution of hydrochloric acid in ether areadded to a solution of 13.4 g of the compound obtained in the precedingstep in 200 ml of MeOH, and the reaction mixture is left stirring for 1hour at RT. It is concentrated under vacuum, the residue is taken up inMeOH and the mixture is again evaporated under vacuum. 11.70 g of theexpected product are obtained, which is used in the next step withoutfurther treatment.

C)N-[2-(3,4-Dichlorophenyl)-4-(methanesulphonyloxy)butyl]-N-methyl-2-(3-isopropoxyphenyl)acetamide.

6.68 g of triethylamine are added to a solution of 11.70 g of thecompound obtained in the preceding step in 100 ml of DCM, and a solutionof 6.94 g of methanesulphonyl chloride in 30 ml of DCM is then addeddropwise. The reaction mixture is left stirring for 6 hours at RT andconcentrated under vacuum. The residue is extracted with AcOEt, themixture is washed with water and with saturated sodium chloride solutionand dried over magnesium sulphate and the solvent is evaporated offunder vacuum. The residue is chromatographed on silica, eluting with aDCM/MeOH (99:1; v/v) mixture. 13.04 g of the expected product areobtained in the form of an oil.

Proton NMR spectrum at 200 MHz in DMSO-d₆.

δ: 1.3 ppm: d: 6 H

2.05 ppm: mt: 2 H

2.8 ppm: sd: 3 H

3 to 4.3 ppm: uc: 10 H

4.6 ppm: sept: 1 H

6.4 to 7.9 ppm: uc: 7 H

D)N-[4-[4-(Carboxymethyl)-4-phenyl-1-piperidyl]-2-(3,4-dichlorophenyl)butyl]-N-methyl-2-(3-isopropoxyphenyl)acetamidehydrochloride.

1.5 g of potassium tert-butylate and then a solution of 1.5 g of thecompound obtained in the preceding step in 10 ml of DMF are added to asolution of 2 g of the compound obtained in PREPARATION 1.22 in 14 ml ofDMF, and the reaction mixture is heated to 80° C. for 3 hours. It ispoured into a pH 7 buffer solution, the product is extracted with DCM,the organic phase is washed with water and with 2N HCl solution anddried over MgSO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica H, eluting with a DCM/MeOH (95:5;v/v) mixture. 0.62 g of the expected product is obtained.

Proton NMR spectrum at 200 MHz in DMSO-d₆.

δ: 1.0 to 1.4 ppm: 2d: 6 H

1.5 to 2.45 ppm: uc: 6 H

2.5 to 3.9 ppm: uc: 16 H

4.6 ppm: sept: 1 H

6.4 to 7.8 ppm: uc: 12 H.

EXAMPLE 20

N-[2-(3,4-Difluorophenyl)-4-[4-(methoxycarbonylamino)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride hemihydrate.

A) N-[2-(3,4-Difluorophenyl)-4-(tetrahydro-2-pyranyloxy)butyl]benzamide.

A solution of 19 g of the compound obtained in PREPARATION 2.4 and 8.06g of triethylamine in 250 ml of DCM is cooled to 0-5° C., a solution of9.82 g of benzoyl chloride in 50 ml of DCM is added dropwise and thereaction mixture is then concentrated under vacuum. The residue isextracted with ether, the organic phase is washed with water, with 10%NaOH solution, with water and with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum. 26 g of theexpected product are obtained.

B)N-[2-(3,4-Difluorophenyl)-4-(tetrahydro-2-pyranyloxy)butyl]-N-methylbenzamide.

A solution of 26 g of the compound obtained in the preceding step in 80ml of DMF is added dropwise to a suspension of 4.4 g of 55% sodiumhydride in oil in 50 ml of DMF, and the reaction mixture is leftstirring for 30 minutes at RT. It is cooled in a water bath, a solutionof 19 g of methyl iodide in 50 ml of DMF is added dropwise and themixture is left stirring overnight at RT. It is concentrated undervacuum, the residue is taken up in water, the product is extracted withDCM, the organic phase is washed twice with water and with saturatedNaCl solution and dried over MgSO₄ and the solvent is evaporated offunder vacuum. 27 g of the expected product are obtained.

C) N-[2-(3,4-Difluorophenyl)-4-hydroxybutyl]-N-methylbenzamide.

A stream of HCl gas is bubbled into a solution of 27 g of the compoundobtained in the preceding step in 500 ml of MeOH until the pH<1, and themixture is left stirring for 15 minutes at RT. It is concentrated undervacuum, the residue is taken up with a saturated solution of HCl gas inMeOH and the solvent is evaporated off under vacuum. The residue isextracted with DCM, the organic phase is washed twice with 5% NaHCO₃solution and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. 15.9 g of the expected productare obtained after solidification in cyclohexane.

D)N-[2-(3,4-Difluorophenyl)-4-(methanesulphonyloxy)butyl]-N-methylbenzamide.

A solution of 6 g of the compound obtained in the preceding step and2.27 g of triethylamine in 200 ml of DCM is cooled to 0-5° C., asolution of 2.37 g of methanesulphonyl chloride in 20 ml of DCM is addeddropwise and the reaction mixture is then concentrated under vacuum. Theresidue is taken up in water, the product is extracted with AcOEt, theorganic phase is washed three times with water, with 5% NaHCO₃ solution,with water and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. 7.8 g of the expected productare obtained.

E)N-[2-(3,4-Difluorophenyl)-4-[4-(methoxycarbonylamino)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride hemihydrate.

This compound is prepared according to the procedure described in step Dof Example 15, from 1.2 g of the compound obtained in the precedingstep, 1.43 g of the compound obtained in PREPARATION 1.5 and 1.42 g ofK₂ CO₃ in 20 ml of a DMF/acetonitrile (50:50; v/v) mixture. 1.18 g ofthe expected product are obtained, m.p.=165° C.

By working according to the procedures described in the above EXAMPLES,starting from the piperidines described in the above PREPARATIONS, thecompounds according to the invention collated in TABLE I below areprepared.

                                      TABLE I                                     __________________________________________________________________________    1  STR53##                                                                       -                                                                                                           Solvate;                                       EXAMPLES Y Ar.sub.1 M.p. °C. or NMR                                  __________________________________________________________________________      21 (a)                                                                                                       2  STR54##                                                                    3  1 H.sub.2 O 130                              - *22 (a)                                                                                                   4  STR56##                                                                    3  0.5 H.sub.2 O 165                            - 23 (a)                                                                                                    5  STR58##                                                                    3  1 H.sub.2 O 152                              - 24 (a)                                                                                                    6  STR60##                                                                    3  0.5 H.sub.2 O 138                            - 25 (b)                                                                                                    7  STR62##                                                                    3  1 H.sub.2 O 112-114                          - 26 (b)                                                                                                    8  STR64##                                                                    9  0.5 H.sub.2 O 130                            - 27 (b)                                                                                                    0  STR66##                                                                    9  0.5 H.sub.2 O 147                            - 28 (b)                                                                                                    1  STR68##                                                                    9  0.5 H.sub.2 O 145                            - 29 (b)                                                                                                    2  STR70##                                                                    9  0.5 H.sub.2 O 140                            - 30 (b)                                                                                                    3  STR72##                                                                    9  1 H.sub.2 O 144                           __________________________________________________________________________

(a) This compound is prepared according to the procedure described inEXAMPLE 17.

(b) This compound is prepared according to the procedure described instep D of EXAMPLE 15.

EXAMPLE 31

1-Benzyl-5-(3,4-difluorophenyl)-5-[2-(4-(N,N-dimethylcarbamoyl)-4-phenyl-1-piperidyl]ethyl]-2-piperidonehydrochloride hemihydrate.

A) 1-Benzyl-5-(3,4-difluorophenyl)-5-(2-hydroxyethyl)-2-piperidone.

2.35 g of potassium tert-butylate are added at RT to a solution of 6.78g of the compound obtained in PREPARATION 2.5 in 50 ml of THF, and themixture is left stirring for 5 minutes at RT. A solution of 3.59 g ofbenzylbromide in 10 ml of THF is then added dropwise, and the mixture isleft stirring for 1 hour at RT and heated to reflux for 30 minutes. Itis concentrated under vacuum, the residue is extracted with ether, theorganic phase is washed with a pH 4 buffer solution, twice with waterand twice with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The oil obtained (8.5 g) isdissolved in MeOH, a stream of HCl gas is bubbled through until the pH=1and the mixture is concentrated under vacuum. 4.8 g of the expectedproduct are obtained after crystallization in AcOEt, m.p.=153-154° C.

B)1-Benzyl-5-(3,4-difluorophenyl)-5-[2-(methanesulphonyloxy)ethyl]-2-piperidone.

A solution of 1 g of the compound obtained in the preceding step and0.35 g of triethylamine in 100 ml of DCM is cooled to 0-5° C., asolution of 0.36 g of methanesulphonyl chloride in 10 ml of DCM is addeddropwise and the mixture is concentrated under vacuum. The residue istaken up in water, the product is extracted with AcOEt, the organicphase is washed with water, with 5% NaHCO₃ solution, with water and withsaturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. 1.2 g of the expected product are obtained.

C)1-Benzyl-5-(3,4-difluorophenyl)-5-[2-[4-(N,N-dimethylcarbamoyl]-4-phenyl-1-piperidyl]ethyl]-2-piperidonehydrochloride hemihydrate.

A mixture of 1.2 g of the compound obtained in the preceding step, 0.8 gof the compound obtained in PREPARATION 1.23 and 1.37 g of K₂ CO₃ in 10ml of a DMF/acetonitrile (50:50; v/v) mixture is heated to 100° C. for 3hours. The reaction mixture is concentrated under vacuum, the residue istaken up in water, the product is extracted with AcOEt, the organicphase is washed with water and with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica, eluting with DCM and then with a DCM/MeOH(96:4; v/v) mixture. The product obtained is dissolved in AcOEt, astream of HCl gas is bubbled through until the pH=1, ether is then addedand the mixture is concentrated under vacuum. 0.65 g of the expectedproduct is obtained after solidification in ether, m.p.=154° C.

By working according to the procedure described in step C of EXAMPLE 31,starting from the compound obtained in step B of EXAMPLE 31 and thepiperidines described in the preparations, the compounds according tothe invention collated in TABLE II below are prepared.

                                      TABLE II                                    __________________________________________________________________________    4  STR74##                                                                       -                                                                                                         Solvate;                                         EXAMPLES Y Ar.sub.1 M.p. ° C. or NMR                                 __________________________________________________________________________      32                                                                                                         7  STR75##                                                                    9  1 H.sub.2 O 160                                - 33                                                                                                      1  STR77##                                                                    9  0.5 H.sub.2 O 162                              - 34                                                                                                      3  STR79##                                                                    9  13880##                                     __________________________________________________________________________

EXAMPLE 35

3-(3,4-Dichlorophenyl)-3-[2-[4-(2-hydroxyethyl)-4-phenyl-1-piperidyl]ethyl]-1-[2-(3-isopropoxyphenyl]acetyl]piperidinehydrochloride monohydrate.

A)3-(3,4-Dichlorophenyl)-1-[2-(3-isopropoxyphenyl)-acetyl]-3-[2-(tetrahydro-2-pyranyloxy)ethyl]-piperidine.

5.9 g of 3-isopropoxyphenylacetic acid and 21.6 g of BOP are added to asolution of 17.5 g of the compound obtained in PREPARATION 2.6 in 100 mlof DCM. The reaction mixture is left stirring for 1 hour at RT andconcentrated under vacuum. The residue is taken up in AcOEt, the organicphase is washed with water, with 10% NaOH solution, with water, with apH 2 buffer solution and with saturated sodium chloride solution anddried over sodium sulphate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica, eluting with DCM andthen with a DCM/AcOEt mixture gradient from (99:1; v/v) to (75:25; v/v).21.5 g of the expected product are obtained, which is used in the nextstep without further treatment.

B)3-(3,4-Dichlorophenyl)-3-(2-hydroxyethyl)-1-[2-(3-isopropoxyphenyl)acetyl]piperidine.

A mixture of 21.5 g of the compound obtained in the preceding step, 0.2g of Amberlyst® and 75 ml of MeOH is heated to reflux for 4 hours. Thereaction mixture is filtered through Celite® and the filtrate isevaporated under vacuum. 18.2 g of the expected product are obtained,which is used in the next step without further treatment.

C)3-(3,4-Dichlorophenyl)-1-[2-(3-isopropoxyphenyl)-acetyl]-3-[2-(methanesulphonyloxy)ethyl]-piperidine.

4.4 g of triethylamine are added to a solution, cooled to 0° C., of 18.2g of the compound obtained in the preceding step in 75 ml of DCM, and asolution of 4.4 g of methanesulphonyl chloride in 20 ml of DCM is thenadded dropwise. The reaction mixture is left stirring for 1 hour andconcentrated under vacuum. The residue is taken up in ether, the mixtureis washed with water and dried over sodium sulphate and the solvent isevaporated off under vacuum. 20 g of the expected product are obtainedin the form of an oil.

Proton NMR spectrum at 200 MHz in DMSO-d₆.

δ: 0.8 to 2.4 ppm: uc: 12 H

3.1 ppm: s: 3 H

3.1 to 4.8 ppm: uc: 9 H

6.5 to 7.9 ppm: uc: 7 H.

D)3-(3,4-Dichlorophenyl)-3-[2-[4-(2-hydroxyethyl)-4-phenyl-1-piperidyl]ethyl]-1-[2-(3-isopropoxyphenyl)acetyl)piperidinehydrochloride monohydrate.

A mixture of 2.4 g of the compound obtained in the preceding step and3.2 g of the compound obtained in PREPARATION 1.24 in 4 ml of DMF isheated to 80° C. for 3 hours. After cooling, the reaction mixture ispoured into water, the mixture is extracted with AcOEt, the organicphase is washed with water and dried over Na₂ SO₄ and the solvent isevaporated off under vacuum. The product obtained is dissolved in DCM,ethereal hydrogen chloride is added until the pH=1 and the precipitateformed is drained. 1 g of the expected product is obtained.

Proton NMR spectrum at 200 MHz in DMSO-d₆.

δ: 0.7 to 4.8 ppm: uc: 34 H

6.4 to 7.8 ppm: uc: 12 H

10.3 ppm: s: 1 H.

EXAMPLE 36

3-[2-[4-(2-Acetoxyethyl)-4-phenyl-1-piperidyl]-ethyl]-3-(3,4-dichlorophenyl)-1-[2-(3-isopropoxyphenyl)acetyl]piperidinehydrochloride monohydrate.

A mixture of 0.7 g of the compound obtained in EXAMPLE 35 and 2 ml ofacetyl chloride in 15 ml of chloroform is heated to reflux for15minutes. The mixture is concentrated under vacuum, the residue isextracted with AcOEt, the organic phase is washed with water, with 5%NaHCO₃ solution and with water and dried over Na₂ SO₄ and the solvent isevaporated off under vacuum. The product obtained is dissolved in DCM,ethereal hydrogen chloride is added until the pH=1 and the precipitateformed is drained. 0.4 g of the expected product is obtained.

Proton NMR spectrum at 200 MHz in DMSO-d₆.

δ: 0.8 to 4.8 ppm: uc: 36 H

6.4 to 7.8 ppm: uc: 12 H

10.2 ppm: s: 1 H.

EXAMPLE 37

N-[4-[4-(2-Amino-4-thiazolyl)-4-phenyl-1-piperidyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamidedihydrochloride sesquihydrate, (-) isomer.

A)N-[2-(3,4-Dichlorophenyl)-4-(methanesulphonyloxy)butyl]-N-methylbenzamide,(-) isomer.

The preparation of this compound is described in Patent ApplicationEP-A-0474561.

B)N-[4-[4-(2-Amino-4-thiazolyl)-4-phenyl-1-piperidyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamidedihydrochloride sesquihydrate, (-) isomer.

A mixture of 1.1 g of the compound obtained in the preceding step, 0.74g of the compound obtained in PREPARATION 1.25 in free base form and0.65 g of K₂ CO₃ in 10 ml of a DMF/acetonitrile (50:50; v/v) mixture isheated to 100° C. for 3 hours. After cooling at RT, the reaction mixtureis poured into water, the product is extracted with AcOEt, the organicphase is washed twice with water and with saturated NaCl solution anddried over MgSO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica H, eluting with DCM and then with aDCM/MeOH (96:4; v/v) mixture. The product obtained is dissolved inacetone, ethereal hydrogen chloride is added until the pH=1 and theprecipitate form is drained. 0.79 g of the expected product is obtained,m.p.=172-174° C.

EXAMPLE 38

N-[2-(3,4-Dichlorophenyl)-4-[4-(2-diethylamino)-4-thiazolyl]-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidedihydrochloride, (-) isomer.

This compound is prepared according to the procedure described inEXAMPLE 5, from 1.72 g of the compound obtained in step B of EXAMPLE 1,2 g of the compound obtained in PREPARATION 1.26, 1.74 g of K₂ CO₃ and16 ml of a DMF/acetonitrile (50:50; v/v) mixture. 1.6 g of the expectedproduct are obtained, m.p.=128-129° C.

[α]_(D) ²⁰ =-14.6° (c=0.5; MeOH).

EXAMPLE 39

5-[2-[4-(2-Amino-4-thiazolyl)-4-phenyl-1-piperidyl]ethyl]-1-benzyl-5-(3,4-difluorophenyl)-2-piperidonedihydrochloride monohydrate.

This compound is prepared according to the procedure described in step cof EXAMPLE 31, from 1.5 g of the compound obtained in step B of EXAMPLE31, 1.1 g of the compound obtained in PREPARATION 1.25 in free baseform, 1 g of K₂ CO₃ and 10 ml of a DMF/acetonitrile (50:50; v/v)mixture. 0.96 g of the expected product is obtained after solidificationin acetone, m.p.=208° C.

EXAMPLE 40

1-Benzyl-5-(3,4-difluorophenyl)-5-[2-[4-[2-(dimethylamino)-4-thiazolyl]-4-phenyl-1-piperidyl]-ethyl]-2-piperidonedihydrochloride hemihydrate.

This compound is prepared according to the procedure described in step Cof EXAMPLE 31, from 1 g of the compound obtained in step P of EXAMPLE31, 1.3 g of the compound obtained in PREPARATION 1.27 and 1.4 g of K₂CO₃ in 20 ml of a DMF/acetonitrile (50:50; v/v) mixture. 0.9 g of theexpected product is obtained after crystallization in AcOEt,m.p.=140-142° C.

EXAMPLE 41

N-[4-[4-(2-Amino-1,3,4-oxadiazol-5-yl)-4-phenyl-1-piperidyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamidedihydrochloride dihydrate, (-) isomer.

This compound is prepared according to the procedure described inEXAMPLE 5, from 1.72 g of the compound obtained in step B of EXAMPLE 1,1.75 g of the compound obtained in PREPARATION 1.28, 1.74 g of K₂ CO₃and 16 ml of a DMF/acetonitrile (50:50; v/v) mixture. 0.95 g of theexpected product is obtained, m.p.=158° C.

[α]_(D) ²⁰ =-26.8° (c=0.5; MeOH).

EXAMPLE 42

N-[2-(3,4-Dichlorophenyl)-4-[4-(3,3-dimethylcarbazoyl)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride dihydrate, (-) isomer.

This compound is prepared according to the procedure described inEXAMPLE 5, from 1.72 g of the compound obtained in step B of EXAMPLE 1,1.76 g of the compound obtained in PREPARATION 1.29, 1.74 g of K₂ CO₃and 16 ml of a DMF/acetonitrile (50:50; v/v) mixture. 1.35 g of theexpected product are obtained, m.p.=153° C.

[α]_(D) ²⁰ =-26.0° (c=0.5; MeOH).

EXAMPLE 43

N-[2-(3,4-Dichlorophenyl)-4-[4-(3-ethyl-1-methylureido)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride monohydrate, (-) isomer.

This compound is prepared according to the procedure described inEXAMPLE 5, from 1.72 g of the compound obtained in step B of EXAMPLE 1,1.82 g of the compound obtained in PREPARATION 1.30, 1.74 g of K₂ CO₃and 16 ml of a DMF/acetonitrile (50:50; v/v) mixture. 0.8 g of theexpected product is obtained after crystallization in ether,m.p.=128-130° C.

[α]_(D) ²⁰ =-24.7° (c=0.5; MeOH).

EXAMPLE 44

1-Benzyl-5-(3,4-difluorophenyl)-5-[2-[4-(methoxycarbonylamino)-4-phenyl-1-piperidyl]ethyl]-2-piperidonehydrochloride monohydrate.

This compound is prepared according to the procedure described in step Cof EXAMPLE 31, from 1.2 g of the compound obtained in step B of EXAMPLE31, 1.38 g of the compound obtained in PREPARATION 1.5, 1.37 g of K₂ CO₃and 20 ml of a DMF/acetonitrile (50:50; v/v) mixture. 0.52 g of theexpected product is obtained, m.p.=150° C.

EXAMPLE 45

1-Benzyl-5-[2-[4-(3-cyclopentylureido)-4-phenyl-1-piperidyl]ethyl]-5-(3,4-difluorophenyl)-2-piperidonehydrochloride monohydrate.

This compound is prepared according to the procedure described in step Cof EXAMPLE 31, from 1 g of the compound obtained in step B of EXAMPLE31, 1.3 g of the compound obtained in PREPARATION 1.9, 1.14 g of K₂ CO₃and 20 ml of a DMF/acetonitrile (50:50; v/v) mixture. 0.68 g of theexpected product is obtained, m.p.=170° C.

EXAMPLE 46

N-[4-[4-(2-Furoylamino)-4-phenyl-1-piperidyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamidehydrochloride sesquihydrate, (-) isomer.

A)N-[4-(4-Amino-4-phenyl-1-piperidyl)-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide,(-) isomer.

This compound is prepared according to the procedure described inEXAMPLE 5, from 6.3 g of the compound obtained in step B of EXAMPLE 1,7.89 g of the compound obtained in PREPARATION 1.31, 7.06 g of K₂ CO₃and 30 ml of a DMF/acetonitrile (50:50; v/v) mixture. The product ischromatographed on silica, eluting with a DCM/MeOH mixture from (95:5;v/v) to (85:15; v/v). 2.9 g of the expected product are obtained in theform of an oil.

B)N-[4-[4-(2-Furoylamino)-4-phenyl-1-piperidyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamidehydrochloride sesquihydrate, (-) isomer.

A solution of 1.14 g of the compound obtained in the preceding step and0.45 g of triethylamine in 10 ml of DCM is cooled to 5° C., 0.29 g of2-furoyl chloride is added and the mixture is left stirring whileallowing the temperature to rise to RT. The mixture is concentratedunder vacuum, the residue is extracted with DCM, the organic phase iswashed with water, with 5% NaHCO₃ solution, with water and withsaturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is chromatographed on silica H,eluting with DCM and then with a DCM/MeOH (97:3; v/v) mixture. Theproduct obtained is dissolved in AcOEt, a stream of HCl gas is bubbledthrough until the pH=1, ether is then added and the precipitate formedis drained. 0.91 g of the expected product is obtained, m.p.=161-163° C.

[α]_(D) ²⁰ =-22.6° (c=0.5; MeOH).

EXAMPLE 47

N-[4-[4-Benzyl-4-(ethoxycarbonylamino)-1-piperidyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamidehydrochloride hemihydrate, (-) isomer.

This compound is prepared according to the procedure described in step Cof Example 1, from 0.5 g of the compound obtained in step B of EXAMPLE1, 0.5 g of the compound obtained in PREPARATION 1.32 and 0.54 g of K₂CO₃ in 5 ml of DMF. 0.33 g of the expected product is obtained,m.p.=134° C. (dec.).

[α]_(D) ²⁰ =-22.1° (c=0.5; MeOH).

EXAMPLE 48

N-[4-[4-[N-(1-Pyrrolidinyl)carbamoyl]-4-phenyl-1-piperidyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamidedihydrochloride dihydrate, (-) isomer.

This compound is prepared according to the procedure described inEXAMPLE 5, from 1.58 g of the compound obtained in step B of EXAMPLE 1,1.6 g of the compound obtained in PREPARATION 1.33, 1.28 g of K₂ CO₃ and10 ml of a DMF/acetonitrile (50:50; v/v) mixture. 0.99 g of the expectedproduct is obtained, m.p.=150-152° C.

[α]_(D) ²⁰ =-5.75° (c=0.5; MeOH).

EXAMPLE 49

N-[4-[4-(3-Acetylcarbazoyl)-4-phenyl-1-piperidyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamidehydrochloride 2.5 hydrate, (-) isomer.

This compound is prepared according to the procedure described inEXAMPLE 5, from 1.22 g of the compound obtained in step B of EXAMPLE 1,1.15 g of the compound obtained in PREPARATION 1.34, 0.94 g of K₂ CO₃and 10 ml of a DMF/acetonitrile (50:50; v/v) mixture. 0.69 g of theexpected product is obtained, m.p.=145-147° C.

[α]_(D) ²⁰ =-0.3° (c=0.5; MeOH).

EXAMPLE 50

1-[2-(3-Chlorophenyl)acetyl]-3-(3,4-dichlorophenyl)-3-[2-[4-(N,N-dimethylcarbamoyl)-4-phenyl-1-piperidyl]ethyl]piperidinehydrochloride monohydrate, (-) isomer.

A)1-[2-(3-Chlorophenyl)acetyl]-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidine,(-) isomer.

7 g of triethylamine and 16.9 g of BOP are added to a solution of 9.6 gof the compound obtained in PREPARATION 2.7 in 300 ml of DCM, themixture is then cooled to 5° C., a solution of 5.9 g of3-chlorophenylacetic acid in 30 ml of DCM is added dropwise and themixture is left stirring for 3 hours while allowing the temperature torise to RT. The mixture is concentrated under vacuum, the residue isextracted with ether, the organic phase is washed with water, with 2NHCl solution, with saturated NaCl solution, with 10% NaOH solution andwith saturated NaCl solution and dried over Na₂ SO₄ and the solvent isevaporated off under vacuum. 15.14 g of the expected product areobtained.

[α]_(D) ²⁰ =-23.8° (c=0.5; MeOH).

B)1-[2-(3-Chlorophenyl)acetyl]-3-(3,4-dichlorophenyl)-3-[2-(methanesulphonyloxy)ethyl]-piperidine.

A solution of 13.44 g of the compound obtained in the preceding step and4.8 ml of triethylamine in 80 ml of DCM is cooled to 0° C., a solutionof 2.6 ml of methanesulphonyl chloride in 80 ml of DCM is added dropwiseand the mixture is left stirring while the temperature is allowed torise to RT. The mixture is concentrated under vacuum, the residue isextracted with AcOEt, the organic phase is washed with water, with 2NHCl solution, with water and with saturated NaCl solution and dried overNa₂ SO₄ and the solvent is evaporated off under vacuum. 16.39 g of theexpected product are obtained.

C)1-[2-(3-Chlorophenyl)acetyl]-3-(3,4-dichlorophenyl)-3-[2-[4-(N,N-dimethylcarbamoyl)-4-phenyl-1-piperidyl]ethyl]piperidinehydrochloride monohydrate, (-) isomer.

A mixture of 1.5 g of the compound obtained in the preceding step, 0.78g of the compound obtained in PREPARATION 1.23 and 0.82 g of K₂ CO₃ in10 ml of a DMF/acetonitrile (50:50; v/v) mixture is heated to 100° C.for 4 hours. After cooling, the reaction mixture is poured into water,the product is extracted with AcOEt, the organic phase is washed withwater and with saturated NaCl solution and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H, eluting with a DCM/MeOH mixture from (99:1; v/v) to (96:4;v/v). The product obtained is dissolved in AcOEt, ethereal hydrogenchloride is added until the pH=1 and the precipitate formed is drained.1.15 g of the expected product are obtained after cyrstallization inether, m.p.=145-150° C.

[α]_(D) ²⁰ =-11.2° (c=0.5; MeOH).

EXAMPLE 51

1-[2-(3-Chlorophenyl)acetyl]-3-(3,4-dichlorophenyl)-3-[2-[4-(1-pyrrolidinylcarbonyl)-4-phenyl-1-piperidyl]ethyl]piperidinehydrochloride monohydrate, (-) isomer.

This compound is prepared according to the procedure described in step Cof EXAMPLE 50, from 1.5 g of the compound obtained in step B of EXAMPLE50, 0.92 g of the compound obtained in PREPARATION 1.21 and 0.82 g of K₂CO₃ in 14 ml of a DMF/acetonitrile (50:50; v/v) mixture. 1.05 g of theexpected product are obtained, m.p.=150-155° C.

[α]_(D) ²⁰ =-12.0° (c=0.5; MeOH).

We claim:
 1. A compound of formula: ##STR81## in which x is zero orone;R'₂ represents a (C₁ -C₇)alkyl; Y' represents a group chosenfrom:Y₃) --O--CH₂ CH₂ --OR₄ ; Y₆) --CH₂)_(q) --OCONH--(C₁ -C₇)alky; Y₁₁)--(CH₂)_(q) --NR₁₃ COOR₁₅ ; Y₁₂) --(CH₂)_(q) --NR₁₃ SO₂ R₁₆ ; Y₁₄)--CONR₁₉ R₂₀ ; Y₁₅) --CH₂ --COOR₂₁ ; Y₁₇) ##STR82## Y₁₈) ##STR83## Y₁₉)--CO--NR₂₅ --NR₂₆ R₂₇ ; in which groups:q is zero, one or two; R₄represents a hydrogen; a (C₁ -C₇)alkyl; a formyl, a (C₁-C₇)alkylcarbonyl; R₁₃ represents a hydrogen or a (C₁ -C₇)alkyl; R₁₅represents a (C₁ -C₇)alkyl or a phenyl; R₁₆ represents a (C₁ -C₇)alkyl;an amino, free or substituted with one or two (C₁ -C₇)alkyls; a phenylunsubstituted or substituted one or more times with a substituent chosenfrom: a halogen atom, a (C₁ -C₇)alkyl, a trifluoromethyl, a hydroxyl, a(C₁ -C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a cyano, a nitro, an amino, free or substitutedwith one or two (C₁ -C₇)alkyls, the said substituents being identical ordifferent; R₁₉ represents a hydrogen or a (C₁ -C₇)alkyl; R₂₀ representsa (C₃ -C₇)cycloalkyl; a (C₃ -C₇)cycloalkylmethyl; a hydroxyl; a (C₁-C₄)alkoxy; a benzyl; a phenyl; a hydrogen; a (C₁ -C₇)alkyl; oralternatively R₁₉ and R₂₀, together with the nitrogen atom to which theyare linked, constitute a heterocycle chosen from: azetidine,perhydroazepine, pyrrolidine, and piperidine R₂₁ represents a hydrogenor a (C₁ -C₇)alkyl; R₂₂ represents a hydrogen or a (C₁ -C₇)alkyl; R₂₃and R₂₄ each independently represent a hydrogen or a (C₁ -C₇)alkyl; R₂can, in addition, represent a formyl or a (C₁ -C₇)alkylcarbonyl; R₂₅represents a hydrogen or a (C₁ -C₇)alkyl; R₂₆ and R₂₇ each independentlyrepresent a hydrogen or a (C₁ -C₇)alkyl; Ar'₁ represents a phenylunsubstituted or substituted one or more times with a substituent chosenfrom: a halogen atom, a hydroxyl, a (C₁ -C₄)alkoxy, a (C₁ -C₄)alkyl, atrifluoromethyl, a methylenedioxy, the said substituents being identicalor different; Ar'₂ represents a phenyl unsubstituted or substituted oneor more times with a substituent chosen from: a halogen atom, ahydroxyl, a (C₁ -C₄)alkoxy, a (C₁ -C₄)alkyl, a trifluoromethyl, amethylenedioxy, the said substituents being identical or different; A'represents a direct bond or a --CH₂ -- group; Z' represents: a phenylunsubstituted or substituted one or more times with a substituent chosenfrom: a halogen atom; a trifluoromethyl; a cyano; a hydroxyl; a nitro; aphenyl unsubstituted or substituted one or more times with a halogen, atrifluoromethyl, a (C₁ -C₄)alkyl, a hydroxyl, a (C₁ -C₄)alkoxy, the saidsubstituents being identical or different; an amino unsubstituted orsubstituted once or twice with a (C₁ -C₄)alkyl; a benzylamino; acarboxyl; a (C₁ -C₁₀)alkyl; a (C₃ -C₈)cycloalkyl unsubstituted orsubstituted one or more times with a methyl; a (C₁ -C₁₀)alkoxy; a (C₃-C₈)cycloalkyloxy unsubstituted or substituted one or more times with amethyl; a mercapto; a (C₁ -C₁₀)alkylthio; a formyloxy; a (C₁-C₆)alkylcarbonyloxy; a formylamino; a (C₁ -C₆)alkylcarbonylamino; abenzoylamino; a (C₁ -C₄)alkoxycarbonyl; a (C₃ -C₇)cycloallyloxycarbonyl;a carbamoyl unsubstituted or substituted once or twice with a (C₁-C₄)alkyl; a ureido unsubstituted or substituted once or twice atposition 3 with a (C₁ -C₄)alkyl or a (C₃ -C₇)cycloalkyl; a(1-pyrrolidinyl)carbonylamino, the said substituents being identical ordifferent; a naphthyl unsubstituted or substituted one or more timeswith a halogen, a trifluoromethyl, a (C₁ -C₄)alkyl, a hydroxyl, a (C₁-C₄)alkoxy; a pyridyl; a thienyl; an indolyl; a quinolyl; abenzothienyl; an imidazolyl; and its salts with inorganic or organicacids.
 2. An optically pure compound according to claim 1, of formula:##STR84## in which: "*" means that the carbon atom thus labelled has theparticular (+) or (-) absolute configuration;x, R'₂, Y', Ar'₁, Ar'₂, A'and Z' are as defined for a compound of formula I'a in claim 1; and itssalts with inorganic or organic acids.
 3. A compound according to claim2, of formula: ##STR85## in which: A' represents a direct bond or a--CH₂ -- group;Z'a represents an unsubstituted phenyl or a phenylsubstituted at position 3 with a halogen or a (C₁ -C₁₀)alkoxy; R₁₉represents a hydrogen or a (C₁ -C₇)alkyl; R₂₀ represents a (C₃-C₇)cycloalkyl; a (C₃ -C₇)cycloalkylmethyl, a hydroxyl; a (C₁-C₄)alkoxy, a benzyl; a phenyl; a hydrogen; a (C₁ -C₇)alkyl; oralternatively R₁₉ and R₂₀, together with the nitrogen atom to which theyare linked, constitute a heterocycle chosen from: azetidine,perhydroazepine, pyrrolidine and piperidine; and its salts withinorganic or organic acids.
 4. A compound according to claim 3, inoptically pure form, and its salts with inorganic or organic acids.
 5. Acompound according to claim 3, wherein:A' is a direct bond; Z' a is aphenyl and R₁₉ and R₂₀ together with the nitrogen atom to which they arelinked, constitute a pyrrolidine group. ##STR86##
 6. A compoundaccording to claim 5 in optically pure form and its salts with organicor in organic acids. 7.N-[2-(3,4-Dichlorophenyl)-4-[4-pyrrolidinycarbonyl)-4-phenyl-1-piperidyl]butyl]-N-methylbenzamidehydrochloride.
 8. Pharmaceutical composition containing as activeprinciple a compound according to claim 1 or one of its pharmaceuticallyacceptable salts in combination with a pharmaceutically acceptablecarrier, excipient or diluent.
 9. Pharmaceutical composition accordingto claim 8, in the form of a dosage unit in which the active principleis mixed with at least one pharmaceutical excipient.
 10. Pharmaceuticalcomposition according to claim 9, containing 0.5 to 1000 mg of activeprinciple.
 11. Pharmaceutical composition according to claim 10,containing 2.5 to 250 mg of active principle.
 12. A pharmaceuticalcomposition which comprises the compound of claim 3 in combination witha pharmaceutically acceptable carrier, excipient or diluent.
 13. Apharmaceutical composition which comprises the compound of claim 5 incombination with a pharmaceutically acceptable carrier, excipient ordiluent.